Nitrotyrosine promotes human aortic smooth muscle cell migration through oxidative stress and ERK1/2 activation.
Nitrotyrosine is a new biomarker of atherosclerosis and inflammation. The objective of this study was to determine the direct effects of free nitrotyrosine on human aortic smooth muscle cell (AoSMC) migration and molecular mechanisms. By a modified Boyden chamber assay, nitrotyrosine significantly increased AoSMC migration in a concentration-dependent manner. For example, nitrotyrosine at 300 nM increased AoSMC migration up to 152% compared with l-tyrosine-treated control cells (P<0.01). Cell wound healing assay confirmed this effect. Nitrotyrosine significantly increased the expression of some key cell migration-related molecules including PDGF receptor-B, matrix metalloproteinase 2 (MMP2) and integrins alphaV and beta3 at both mRNA and protein levels in AoSMC (P<0.01). In addition, nitrotyrosine increased reactive oxygen species (ROS) production in AoSMC by staining with fluorescent dye DCFHDA. Furthermore, nitrotyrosine induced transient phosphorylation of ERK2 by Bio-Plex luminex immunoassay and western blot analysis. AoSMC were able to uptake nitrotyrosine. Antioxidants including seleno-l-methionine and superoxide dismutase mimetic (MnTBAP) as well as ERK1/2 inhibitor PD98059 effectively blocked the promoting effect of nitrotyrosine on AoSMC migration and the mRNA expression of above cell migration-related molecules. Thus, nitrotyrosine directly increases AoSMC migration in vitro and the expression of migration-related molecules through overproduction of ROS and activation of ERK1/2 pathway. Nitrotyrosine may contribute to cardiovascular pathogenesis.


Inferior vena cava stenosis in scimitar syndrome: a case report.
The scimitar syndrome, first described by Chassinat in 1836, consists aessentially of an anomalous pulmonary vein draining whole or part of the right lung into the inferior vena cava. Associated anomalies are frequent, such as hypoplasia of the right lung, dextrocardia, malformations of the right pulmonary artery and bronchial tree, and abnormal arterial supply of the right lung (the so-called sequestration). This article describes a scimitar syndrome associated with stenosis of the inferior vena cava, whose initial diagnosis was made by two-dimensional echocardiographic Doppler color flow mapping. To our knowledge this is the first description of such an unusual association.


Extended honeymoon period in a type 1 diabetic child by Iranian Traditional Medicine treatments, a case report.
We present a 4-year-old newly diagnosed T1DM boy who presented with sever polyuria and polydipsia and HbA1C of 9.3%. Coincident with onset of ITM program insulin doses were tapered and the baby got free from insulin soon. Only three months after traditional anti-diabetic medications, his HbA1C improved to 5.8%.


Quantitative immunoelectron microscopic localization of Na, K-ATPase alpha-subunit in the epithelial cells of rat vestibular apparatus.
Na, K-ATPase was quantitatively localized in the epithelial cells of rat vestibular apparatus such as macula utriculi, macula sacculi and crista ampullaris. Immunogold localization method was carried out at the saturation level of antibody using an affinity purified antibody against the alpha-subunit of rat kidney Na, K-ATPase. Numerous gold particles were found on the basolateral membrane of the dark cells, a small number of gold particles were found on the basolateral membrane of the transitional epithelium cells and hair cells, but the luminal surface membranes of the hair cells, transitional epithelium cells, planum semilunatum cells and dark cells were rarely labeled by gold particles. Significance of the abundant localization of Na, K-ATPase on the basolateral surface of the dark cells in the production of endolymph was discussed.


Aflatoxin B1 disrupts the intestinal barrier integrity by reducing junction protein and promoting apoptosis in pigs and mice.
With the growing diversity and complexity of diet, animals and humans are at risk of exposure to aflatoxin B1 (AFB1), which is a well-known contaminant in the food chain that causes various toxicological effects. The intestine acts as the first barrier against external contaminants, but the effect of AFB1 on intestinal barrier has not been determined. This study aimed to evaluate AFB1 on the intestinal barrier function in vitro and in vivo. In vitro, porcine jejunal epithelial cells (IPEC-J2) were treated with increasing concentrations of AFB1 (10-60 mg/L). In vivo, Kunming (KM) mice were used as controls or gavaged with 1% dimethyl sulfoxide (110 mg/kg b.w.) and AFB1 (0.3 mg/kg b.w.) for 28 days. In IPEC-J2 cells, the cell viability decreased with increasing mycotoxin concentrations, and the viability of IPEC-J2 cells decreased significantly (P < 0.05) when the AFB1 concentrations were greater than 30 mg/L. In addition, quantitative real-time PCR, Western blot analysis, and immunofluorescence results show that AFB1 can downregulate the tight junction proteins and increase the expression levels of Caspase-3 and the ratio of Bax/Bcl-2, suggesting that AFB1 was cytotoxic to IPEC-J2. In vivo, the ratio of villus height to crypt depth, the intestinal wall thickness, the number of intestinal villus per 1000 µm in the jejunum, the expression levels of ZO-1, Claudin-3, Occludin, MUC2, and Caspase-3, and the ratio of Bax/Bcl-2 were significantly affected in mice exposed to AFB1. In vitro and in vivo results showed that the effects of exposure to AFB1 on the intestinal function in the jejunum of KM mice and in the IPEC-J2 was similar, suggesting that AFB1 may adversely affect animal intestine.


Preferential microglial activation associated with pathological alpha synuclein transmission.
Self-proliferation of the pathological form of α-synuclein was identified as one of the main pathophysiological presentations of Parkinson's disease (PD) a decade ago. Although inflammation has also been suggested to contribute to PD pathogenesis, it is unclear whether this is associated with the pathological spread of α-synuclein aggregation. Herein, we evaluated two main neuroinflammatory processes in the striatum-microgliosis and astrogliosis-after the injection of preformed fibrils of α-synuclein into the mouse striatum. Thus, our study demonstrated that microgliosis accompanied α-synuclein propagation, while astrogliosis did not. Therefore, we report a preferential association between microglia and the process of α-synuclein proliferation.


Tiotropium and salmeterol/fluticasone combination do not cause oxygen desaturation in COPD.
It has been documented that tiotropium is less likely to induce oxygen desaturation in stable COPD patients compared to long-acting beta2-agonists (LABAs) and combined administration of a LABA and an inhaled corticosteroid (ICS) reduces the potential for acute effects of LABA on blood-gas tensions. In this study, we have compared the acute effects of tiotropium 18 microg and salmeterol/fluticasone combination (SFC) 50/250 microg on arterial blood gases in 20 patients with stable COPD. Each subject was studied on 2 days, separated from one another by at least 4 days. Blood specimens were taken just before the inhalation and at 15, 30, 60, 180 and 360 min after inhalation of each treatment, and spirometry was performed at the same time points. As expected, both treatments significantly improved FEV1 (greatest changes were 0.20 L, 95% CI: 0.13-0.27 at 360 min after tiotropium; and 0.13 L, 95% CI: 0.06-0.19 at 180 min after SFC). The greatest mean changes from baseline in PaO2 were -1.7 (95% CI: -4.0 to 0.6)mmHg, p=0.134, after tiotropium; -0.8 (95% CI: -2.2 to 0.6)mmHg, after SFC. Both changes were observed after 15 min. Both drugs caused a small decrease in PaCO2 (greater changes: -1.9 (95% CI -3.2 to -0.6)mmHg, p=0.005 at 60 min after tiotropium; and -2.4 (95% CI: -3.5 to -1.3) mmHg, p=0.0002 at 180 min after SFC). These results indicate that both tiotropium and SFC are able to induce a significant long-last bronchodilation without affecting arterial blood gases. Moreover, they confirm that the impact of tiotropium on PaO2 is small and without clinical significance and the addition of a LABA to an ICS can reduce the potentially dangerous acute effect of the LABA on blood gases.


Influence of fetal extracellular volume contraction on renal reabsorption of bicarbonate in fetal lambs.
In order to determine the renal threshold for bicarbonate in the fetal lamb and factors that may influence renal reabsorption of bicarbonate in the fetus, 18 acute fetal lamb preparations (110-140 days of gestation) were studied. In the first series of experiments involving nine fetuses, the renal bicarbonate threshold of normal fetuses varied from 12.0 to 23.5 mM/liter with a mean value of 17.7 +/- 1.37 mM/liter. This is significantly lower (P less than 0.005) than the value measured in five adult sheep of 28.7 +/- 1.68 mM/liter. There was a significant and positive correlation between the fetal plasma bicarbonate at threshold level and the fetal kidney weight, as well as fetal age. In a second series of experiments, the excretion of bicarbonate and sodium was studied in nine fetuses before and after dehydration by peritoneal dialysis. After peritoneal dialysis there was a significant decrease in urinary pH (P less than 0.025), bicarbonate excretion (P less than 0.001), sodium excretion (P less than 0.001), fractional excretion of sodium (P less than 0.01). When glucose was replaced by mannitol in the peritoneal dialysis fluid the effects on bicarbonate reabsorption paralleled those when glucose was present in dialysis fluid. It was also shown that when glucose was given intravenously to the fetus, up to a plasma concentration of 200 mg/100 ml, there was no effect on the fetal renal reabsorption of bicarbonate. These data indicate that the low threshold for bicarbonate reabsorption by the fetal kidney is not due to a limited capacity to increase bicarbonate or sodium reabsorption and suggest that the fetal kidney is able to respond to volume depletion by increasing its reabsorption in bicarbonate and electrolytes.


Gastric emptying in response to IAPP and CCK in rats with subdiaphragmatic afferent vagotomy.
In the subdiaphragmatic vagal deafferentation procedure (SDA), the afferent fibers of the vagus are surgically severed unilaterally where they enter the brain stem. The technique includes a subdiaphragmal truncal vagotomy performed on the contralateral side. This procedure has been used to study the control of food intake, but it has not been used previously to investigate the role of vagal afferent fibers in the control of gastric emptying (GE). The current experiment studied the effect of SDA on the inhibition of GE by islet amyloid polypeptide (IAPP or amylin) and cholecystokinin (CCK) in awake, unrestrained rats with gastric cannulas. The experimental group underwent subdiaphragmatic vagal deafferentation; the control group had sham operations. All rats received 20-min intravenous infusions of IAPP (1, 3, 9, 27, and 81 pmol/kg/min), CCK (3, 30 and 90 pmol/kg/min), and normal saline in random order. Gastric emptying of saline was measured by the phenol red method during the last 5 min of each infusion period. CCK dose-dependently inhibited gastric emptying in both the control and SDA animals. The inhibition of GE by CCK was significantly attenuated by SDA (p<0.01). IAPP also inhibited gastric emptying dose-dependently, but the difference between the SDA and control groups was not significant. The current experiment, which used a different methodology than previous studies, provides support for the hypothesis that the inhibition of gastric emptying by CCK, but not by IAPP, is mediated partly by afferent vagal fibers.


Synthesis and evaluation of biphenyl derivatives as potential downregulators of VEGF protein secretion and telomerase-related gene expressions.
A group of 47 biphenyl functionalized compounds, prepared by means of Suzuki couplings, has been investigated for their cytotoxicity on two tumoral cell lines (HT-29 and MCF-7) and one non tumoral cell line (HEK-293). 29 selected compounds have been investigated for their ability to inhibit the production of the vascular endothelial growth factor (VEGF). Subsequently, the capacity of the compounds to downregulate the expression of the VEGF, h-TERT and c-Myc genes, the two latter involved in the control of the activation of telomerase, has also been determined.


Polyamine homeostasis in tomato biotic/abiotic stress cross-tolerance.
Adverse conditions and biotic strain can lead to significant losses and impose limitations on plant yield. Polyamines (PAs) serve as regulatory molecules for both abiotic/biotic stress responses and cell protection in unfavourable environments. In this work, the transcription pattern of 24 genes orchestrating PA metabolism was investigated in Cucumber Mosaic Virus or Potato Virus Y infected and cold stressed tomato plants. Expression analysis revealed a differential/pleiotropic pattern of gene regulation in PA homeostasis upon biotic, abiotic or combined stress stimuli, thus revealing a discrete response specific to diverse stimuli: (i) biotic stress-influenced genes, (ii) abiotic stress-influenced genes, and (iii) concurrent biotic/abiotic stress-regulated genes. The results support different roles for PAs against abiotic and biotic stress. The expression of several genes, significantly induced under cold stress conditions, is mitigated by a previous viral infection, indicating a possible priming-like mechanism in tomato plants pointing to crosstalk among stress signalling. Several genes and resulting enzymes of PA catabolism were stimulated upon viral infection. Hence, we suggest that PA catabolism resulting in elevated H2O2 levels could mediate defence against viral infection. However, after chilling, the activities of enzymes implicated in PA catabolism remained relatively stable or slightly reduced. This correlates to an increase in free PA content, designating a per se protective role of these compounds against abiotic stress.


Cell membrane water permeability of rabbit cortical collecting duct.
The water permeability (Posm) of the cell membranes of isolated perfused rabbit cortical collecting ducts was measured by quantitative light microscopy. Water permeability of the basolateral membrane, corrected for surface area, was 66 microns X sec-1 for principal cells and 62.3 microns X sec-1 for intercalated cells. Apical membrane Posm values corrected for surface area, were 19.2 and 25 microns X sec-1 for principal and intercalated cells, respectively, in the absence of antidiuretic hormone (ADH). Principal and intercalated cells both responded to ADH by increasing Posm of their apical membranes to 92.2 and 86.2 microns X sec-1, respectively. The ratio of the total basolateral cell membrane osmotic water permeability to that of the apical cell membrane was approximately 27:1 in the absence of ADH and approximately 7:1 in the presence of the hormone for both cell types. This asymmetry in water permeability is most likely due to the fact that basolateral membrane surface area is at least 7 to 8 times greater than that of the apical membrane. Both cell types exhibited volume regulatory decrease when exposed to dilute serosal bathing solutions. Upon exposure to a hyperosmotic serosal bath (390 mosM), principal cells did not volume regulate while two physiologically distinct groups of intercalated cells were observed. One group of intercalated cells failed to volume regulate; the second group showed almost complete volume regulatory increase behavior.


Nociceptive behavioral responses to chemical, thermal and mechanical stimulation after unilateral, intrastriatal administration of 6-hydroxydopamine.
The basal ganglia are involved not only with motor processes such as posture, pre-movement planning and movement initiation, but also with the processing and modulation of nociceptive somatosensory information. In the current studies, unilateral, intrastriatal 6-hydroxydopamine (6-OHDA) was used to investigate how dopamine depletion alters nociceptive behavioral responses to chemical, thermal and mechanical stimulation in rats. Compared to control rats injected with intrastriatal saline, rats depleted of dopamine displayed increased nociceptive responses to chemical stimulation of the face and hyperalgesic responses to thermal stimulation of the hind paw without alterations in rearing behavior or body weight gain. Minor changes were observed in the response to mechanical stimulation of the hind paws and face. These data provide further evidence that the dopaminergic nigrostriatal pathway plays a role in the modulation of nociceptive information.


[Colorectal cancer].
The current status of laparoscopic surgery for colorectal cancer is herein described. After cholecystectomy, laparoscopic colorectomy, minimally invasive surgery for an infection of the rectum, prepares a patient for endoscopic surgery. Opinion is still divided on the procedure, but it is likely to be recognized as a standard operation at least for early cancer. In recent years, randomized controlled trials have been compared to laparoscopic surgery and open surgery, and the results were almost the same. However, it will be possible for laparoscopic surgery to be performed on advanced cancer patients regularly hereafter. Thus, it is important to consider the technical background evidence and suitable cases.


Off-label use of duct occluder devices to close hemodynamically significant perimembranous ventricular septal defects: A multicenter experience.
We sought to evaluate the feasibility, technical aspects, and outcome of transcatheter perimembranous ventricular septal defect (pmVSD) closure using duct occluder devices with a single retention disc. Use of duct occluder devices to close pmVSD seems a promising alternative therapy. However, limited data exist on this technique. From 2010 to 2016, 222 patients (female 47.7%) were identified from databases of five participating institutions in whom pmVSD closure was attempted using an Amplatzer Duct Occluder I or Lifetech duct occluder device. Patients ranged in age from 0.7 to 52 years (median, 7.0 years) and in weight from 4.0 to 70 kg (median, 18.0 kg). The mean size of the VSD was 6.8 ± 2.2 mm. A large defect (> 6 mm) was present in 137 patients (61.7%). Device closure was successful in 218 patients (98.2%). The 10/8 mm device was used in most patients (n = 85, 38.3%), and the vascular approach was from the femoral vein in 169 patients (76.1%). There were 18 early complications in 17/218 patients (7.8%). Three patients (1.4%) developed complete heart block (transient n = 2; requiring permanent pacing n = 1). Median follow-up was 6 months (6 months-6 years). A mild residual shunt was seen in 10 patients at 6 months follow-up. The immediate results of transcatheter pmVSD closure using a duct occluder device with a single retention disc are promising. It is an effective technique with a lower rate of complications than for other currently available devices.


Association between dairy products consumption and the prevalences of combined prediabetes and type 2 diabetes mellitus in Brazilian adolescents: a cross-sectional study.
The association between dairy products consumption in adults and the likelihood of type 2 diabetes mellitus (T2DM) has been described, but more information on the adolescent population is needed. This nationally representative, cross-sectional school-based study aimed to describe the consumption of dairy products and their subtypes and to evaluate their association with prediabetes and T2DM in adolescents. The Study of Cardiovascular Risks in Adolescents (ERICA) includes adolescents aged 12-17 years. Dairy products consumption was evaluated by 24-h food recall. Associations with fasting glucose, glycated hemoglobin (HbA1c) and insulin resistance, as measured by homeostatic model assessment-insulin resistance (HOMA-IR), were evaluated by multivariate linear regression. Poisson regression was also used to assess the association between dairy products consumption and the combined prevalence of prediabetes and T2DM. Models were adjusted for sociodemographic, nutritional, behavioural and anthropometrics. The final sample analysed consisted of 35 614 adolescents. Total intake of dairy products was inversely associated with fasting blood glucose levels after adjusting for all covariates (β = -0·452, 95 % CI -0·899, -0·005). The associations were stronger for overweight and obese adolescents. Findings were similar for full-fat dairy products and yogurt. Higher consumption of low-fat dairy products and cheese were associated with a 46 % (prevalence ratio, PR 1·46, 95 % CI 1·18, 1·80) and 33 % (PR 1·33, 95 % CI 1·14, 1·57) higher combined prevalence of prediabetes and T2DM, respectively. The total consumption of dairy products and full-fat dairy products was associated with a lower combined prevalence of prediabetes and T2DM, while the consumption of cheese and low-fat dairy products was associated with higher combined prevalence of prediabetes and T2DM in Brazilian adolescents.


Some new results on stability and synchronization for delayed inertial neural networks based on non-reduced order method.
In this paper, without transforming the second order inertial neural networks into the first order differential systems by some variable substitutions, asymptotic stability and synchronization for a class of delayed inertial neural networks are investigated. Firstly, a new Lyapunov functional is constructed to directly propose the asymptotic stability of the inertial neural networks, and some new stability criteria are derived by means of Barbalat Lemma. Additionally, by designing a new feedback control strategy, the asymptotic synchronization of the addressed inertial networks is studied and some effective conditions are obtained. To reduce the control cost, an adaptive control scheme is designed to realize the asymptotic synchronization. It is noted that the dynamical behaviors of inertial neural networks are directly analyzed in this paper by constructing some new Lyapunov functionals, this is totally different from the traditional reduced-order variable substitution method. Finally, some numerical simulations are given to demonstrate the effectiveness of the derived theoretical results.


Acute antipsychotic treatments induce distinct c-Fos expression patterns in appetite-related neuronal structures of the rat brain.
A number of atypical antipsychotic drugs are known to perturb appetite regulation causing greater hyperphagia in humans and rodents than earlier generation typical agents. However, the neuronal structures that underlie hyperphagic effects are poorly understood. Arcuate nucleus (ArcN), paraventricular hypothalamic nucleus (PVN), paraventricular thalamic nucleus (PVA) and nucleus incertus (NI) have been implicated in appetite regulation. The NI is the principal source of the relaxin-3 (RLN3) peptide, which is reported to have orexigenic effects. Moreover, ArcN, PVN, and PVA receive RLN3 immunoreactive fibers from the NI and express relaxin family peptide type 3 (RXFP3) receptor. The present study was designed to evaluate the acute effects of clozapine (atypical), chlorpromazine (typical) and fluphenazine (typical) on c-Fos expression (a marker of neuronal response) in these appetite-related centers of the rat brain. The numbers of c-Fos expressing neurons in these structures were counted in immunofluorescence stained brain sections. Acute treatment with clozapine, chlorpromazine and fluphenazine differentially influenced c-Fos expression in these brain structures. This study is also the first demonstration that antipsychotics influence the NI. The patterns of the effects of these antipsychotics are related to their reported hyperphagic properties.


Left recurrent laryngeal nerve injury following internal mammary artery bypass.
To our knowledge, recurrent laryngeal nerve injury has not been reported previously as a complication of internal mammary artery mobilization for coronary artery bypass. We recently experienced this complication and are presenting a case history of the problem and comments.


Stress-Induced Metabolic Disorder in Peripheral CD4+ T Cells Leads to Anxiety-like Behavior.
Physical or mental stress leads to neuroplasticity in the brain and increases the risk of depression and anxiety. Stress exposure causes the dysfunction of peripheral T lymphocytes. However, the pathological role and underlying regulatory mechanism of peripheral T lymphocytes in mood disorders have not been well established. Here, we show that the lack of CD4+ T cells protects mice from stress-induced anxiety-like behavior. Physical stress-induced leukotriene B4 triggers severe mitochondrial fission in CD4+ T cells, which further leads to a variety of behavioral abnormalities including anxiety, depression, and social disorders. Metabolomic profiles and single-cell transcriptome reveal that CD4+ T cell-derived xanthine acts on oligodendrocytes in the left amygdala via adenosine receptor A1. Mitochondrial fission promotes the de novo synthesis of purine via interferon regulatory factor 1 accumulation in CD4+ T cells. Our study implicates a critical link between a purine metabolic disorder in CD4+ T cells and stress-driven anxiety-like behavior.


Performance evaluation of dual-energy CT and differential phase contrast CT in quantitative imaging applications.
The purpose of this study is to evaluate and compare the quantitative material decomposition performance of the dual-energy CT (DECT) and differential phase contrast CT (DPCT) via numerical observer studies. The electron density ( ρ e $\rho _{{\rm e}}$ ) and the effective atomic number ( Z eff $Z_{{\rm eff}}$ ) are selected as the decomposition bases. The image domain based decomposition algorithms with certain noise suppression are used to extract the ρ e $\rho _{{\rm e}}$ and Z eff $\text{Z}_{{\rm eff}}$ information under three different spatial resolutions (0.3 mm, 0.1 mm, and 0.03 mm). The contrast-to-noise-ratio (CNR) and the numerical human observer model which is sensitive to the noise textures are investigated to compare the quantitative imaging performance of DECT and DPCT under varied radiation dose levels. The model observer results show that the DECT is superior to DPCT at 0.3 mm spatial resolution (300 mm object size); the DECT and DPCT show similar quantitative imaging performance at 0.1 mm spatial resolution (100 mm object size); and the DPCT outperforms the DECT by approximately 1.5 times for the 0.3 mm sized imaging target at 0.03 mm spatial resolution (30 mm object size). In conclusion, the DECT would be recommended to obtain ρ e $\rho _{{\rm e}}$ and Z eff $Z_{{\rm eff}}$ for the low spatial resolution quantitative imaging applications such as the diagnostic CT imaging. Whereas, the DPCT would be recommended for ultra high spatial resolution imaging tasks of small objects such as the micro-CT imaging. This study provides a reference to determine the most appropriate quantitative X-ray CT imaging method for a certain radiation dose level.


The Use of Flow Cytometry for Estimating Genome Sizes and DNA Ploidy Levels in Plants.
Flow cytometry has emerged as a uniquely flexible, accurate, and widely applicable technology for the analysis of plant cells. One of its most important applications centers on the measurement of nuclear DNA contents. This chapter describes the essential features of this measurement, outlining the overall methods and strategies, but going on to provide a wealth of technical details to ensure the most accurate and reproducible results. The chapter is aimed to be equally accessible to experienced plant cytometrists as well as those newly entering the field. Besides providing a step-by-step guide for estimating genome sizes and DNA-ploidy levels from fresh tissues, special attention is paid to the use of seeds and desiccated tissues for such purposes. Methodological aspects regarding field sampling, transport, and storage of plant material are also given in detail. Finally, troubleshooting information for the most common problems that may arise during the application of these methods is provided.


CAR NK Cell Therapy for T Follicular Helper Cells.
T follicular helper (TFH) cells are associated with the development of both autoimmune disease and T cell malignancies. In this issue, Reighard et al.,1 describe the design of PD-L1 chimeric antigen receptor (CAR) NK cells that effectively target and eliminate TFH cells.


Classical- and bioconjugate vaccines: comparison of the structural properties and immunological response.
Glycoconjugate vaccines have been effectively used in humans for about 40 years. The glycoconjugates have substituted plain polysaccharide vaccines that have many limitations, especially in infants. The covalent linking of protein to carbohydrates has allowed to overcome T-cell-dependent type-2 response of sugars. Glycoconjugates can show improved responses (over plain saccharides) also in elderly and immunocompromised (and depending on the endpoint also in immunocompetent adults), but infants represent the main target of these vaccines because of their unique immune system. Differently from the plain polysaccharide vaccines, the glycoconjugates are also able to induce Immunoglobulin G (IgG) response in infants. Recently, vaccines containing conjugates directly expressed in Escherichia coli (bioconjugates) have been tested in the clinic against Shigella dysenteriae type 1, uropathogenic E. coli, and Streptococcus pneumoniae. Here, we report an overall comparison of classical- and bioconjugate vaccines in terms of the structural properties and the immunological response elicited.


Eco-friendly whey/polysaccharide-based hydrogel with poly(lactic acid) for improvement of agricultural soil quality and plant growth.
A set of renewable and biodegradable hydrogels based on acid whey and cellulose derivatives blended with poly(lactic acid) (PLA) were designed as eco-friendly biopolymeric material for sustainable agricultural applications. The physico-chemical properties of the hydrogel were evaluated using scanning electron microscopy (SEM), Fourier transform infrared spectroscopy (FTIR), and rheological measurements. The effect of the whey/polysaccharide/PLA hydrogel on soil quality improvement (water retention study, biodegradability, loading capacity and release of the fertilizers) and the growth pattern of Raphanus sativus and Phaseolus vulgaris has been also studied. The addition of PLA has been found to improve mechanical properties of the hydrogel. The introduction of 20% wt PLA extended decomposition time of hydrogels by 25% which makes the material more stable in the environment and maintaining the soil humidity for longer. The increasing the amount of PLA led to a rise in hydrogel viscosity brought about better entrapment efficiency of the fertilizers (86-92% for KNO3 and 87-96% for urea, resp.) compared to control (82% for KNO3 and 85% for urea, resp.). The novel hydrogels with swelling ratio of up to 500% showed potential as a sustainable water reservoir for plants improving water retention capacity of the soil by 30%.


Liquid chromatographic method for determining added folic acid in fortified cereal products.
Reversed-phase ion-pair high-performance liquid chromatography (HPLC) was coupled with detection by UV absorption (280 nm) for separation and quantitation of added folic acid (FA) in fortified cereal based foods. A simple and rapid liquid-solid extraction method, combined with enzymatic digestion, to recover FA from the sample matrices is also presented. The quantitation of added FA was achieved in products including corn (maize), wheat-, rice- and oat-based cereal breakfast foods fortified at 25% and 100% of the reference daily intake (RDI). The retention time for FA was ca. 15 min, and the detection limit was 2 ng/20 microliters injection for standard FA. When FA was added to unfortified samples of wheat flour at concentrations of 3.08 or 20.0 micrograms/g, recoveries were 93% and 96%, respectively. Comparison of HPLC results with those of a standard microbiological assay has shown quite good agreement (r = 0.998). A solid-phase extraction clean-up procedure has also been developed for use with samples fortified with low levels of FA, where interferences may otherwise hinder quantitation.


Load Monitoring and Its Relationship with Healthcare in Sports.
Load monitoring consists of training/match demand quantification as well as wellness and readiness to maximize the likelihood of optimal athletic performance [...].


Echinomycin in recurrent and metastatic endometrial carcinoma. A phase II trial of the Gynecologic Oncology Group.
Twenty-one evaluable patients with recurrent or metastatic endometrial carcinoma were treated with 1,500 micrograms/m2 of echinomycin every 3 weeks. All patients had received prior chemotherapy. There was one complete response (5%), 95% confidence interval for response is 0.9-22.7%. The major toxicity was nausea and vomiting which was moderate to severe in 42% of patients. Myelosuppression was minimal. Echinomycin, in this dose and schedule, displays minimal activity in patients with advanced endometrial carcinoma who have had prior chemotherapy.


Multivariate analysis of seed chemical diversity among wild fenugreek (Trigonella monantha C. A. Mey.) ecotypes.
Wild fenugreek (Trigonella monantha), a multi-purpose annual plant, has traditionally been used as a food, forage, and medicinal plant. However, the knowledge of the diversity of its chemical characteristics is limited. In this study, 40 wild fenugreek ecotypes collected from their natural habitats in Iran and grown together in field conditions, were analyzed for their seed chemical properties. The ecotypes were cultivated in a randomized complete block design (RCBD) with three replications. The results of ANOVA revealed a significant difference among the ecotypes for all measured characters (P < 0.01). The results showed a high level of diversity among the ecotypes based on the measured characters, including antioxidant activity (48.19 to 86.85%), phenol (0.82 to 1.51 mg gallic acid per g dry weight), flavonoid (1.07 to 3.11 mg quercetin per g dry weight), trigonelline (0.02 to 0.08 mmol/l), 4-hydroxyisoleucine (0.197 to 0.906 mg/g), sucrose (0.13 to 3.77 mM), glucose (1.07 to 12.1 mM), and fructose (13.3 to 45.5 mM). The cluster analysis divided the ecotypes into four groups and the PCA analysis showed that the three first components explained 73% of the total variance among the ecotypes. Also, heat map correlation revealed that many positive and negative correlations were observed among the measured characters. The results did not show a relationship between the amounts of compounds and the place of sample collection. The present study suggests considerable diversity in the seed chemical compositions of the wild fenugreek ecotypes. Therefore, many ecotypes could be useful for medicinal purposes, as well as for human nutrition.


Experience of co-creation of a health plan and support for sustainable physical activity among people with chronic widespread pain: a qualitative interview study in Sweden.
The aim of this study was to gain deeper knowledge about how people with chronic widespread pain (CWP) experience the co-creation of a health plan for sustainable physical activity, working in partnership with a physiotherapist, supported by a digital platform. Qualitative semistructured in-depth individual interviews were analysed with qualitative content analysis. Five primary healthcare centres in western Sweden. The interviewees comprised 19 individuals with CWP who had previously participated in a person-centred intervention involving co-creation of a health plan and support via a digital platform. The interviews were carried out from late 2019 to spring 2020, 1-6 months after the respondents' final follow-up. The analysis resulted in an overarching theme; hope for physical activity that actually works, illustrating the experience of taking part in co-creating a reasonable health plan, based on the respondents' own goals and interests with the potential to actually work. This theme was based on two categories: a plan tailored for me and a frame for participation and accessibility to help fulfil the plan. The digital platform provided a way to participate and an assurance that there was someone there for them if necessary. The co-creation of a health plan nurtured hope of having developed a manageable plan for physical activity that could lead to improved future health and well-being. Digital support may serve as a valuable complement in order to sustain and adjust the planned physical activity. ClinicalTrials.gov Identifier: NCT03434899.


Composition of chlorinated dibenzodioxins and dibenzofurans in various samples.
The composition of chlorinated dibenzodioxins (CDD) and dibenzofurans (CDF) in terms of the degree of chlorination (tetra- to octachloro-) is displayed by principal components projection. Chlorinated dibenzodioxins and dibenzofurans with 4-6 chlorines are the main classes in samples of crabs and lobsters, CCD with 7 and 8 chlorines prevail in human samples. Chlorinated dibenzodioxins and dibenzofurans from incinerator ash are similar to those from human tissues. Those from gaseous incinerator emissions are enriched in less chlorinated classes and resemble residues isolated from conifer needles. Compositions of CDD and CDF in ambient air vary depending on both local and remote sources.


Corneal melting and perforation in Stevens Johnson syndrome following topical bromfenac use.
We report a case of a 20-year-old woman with tear deficiency secondary to Stevens Johnson syndrome who developed bilateral corneal melting following use of bromfenac (Xibrom), a nonsteroidal antiinflammatory drug (NSAID), for 2 weeks. The patient presented with complaints of light sensitivity and pain in the right eye. The slitlamp examination revealed a corneal perforation with iris plug in the right eye and an 85% thinned cornea in the left eye. She was admitted to the hospital, where Xibrom was discontinued, therapeutic contact lenses were placed, and a regimen of topical antibiotic agents was instituted. One day after admission, penetrating keratoplasty was performed in the right eye, an amniotic membrane was placed in the left eye, and tarsorrhaphy was performed bilaterally. The clinical features of this case highlight the importance of being selective when administering NSAIDs in patients with a compromised ocular surface.


An enzyme immunoassay for the quantitation of dihydropteridine reductase.
A competitive, enzyme-linked immunosorbent assay for the quantitative determination of dihydropteridine reductase (DHPR) is described. This highly sensitive method can determine the content of DHPR protein in tissue preparations independently of the enzymatic activity of the protein molecule. The method involves initial incubation of samples containing soluble enzyme in microtiter plates coated with purified goat antibodies to rat DHPR and further incubation with DHPR conjugated to alkaline phosphatase. The assay is used to study the ontogeny of DHPR in rat liver.


Induction of the heat shock response in vivo inhibits NF-kappaB activity and protects murine liver from endotoxemia-induced injury.
Liver plays an important role in the pathogenesis of sepsis by releasing various cytokines and producing acute phase proteins. Heat shock preconditioning is reported to be effective in protection of lung and liver from injury in sepsis and in endotoxemia models, but the exact mechanism is still not fully understood. We report here on the effects of the heat shock response (HSR) induced by sodium arsenite on endotoxemia-induced liver injury as well as hepatic NF-kappaB activation and proinflammatory cytokine expression. Prior induction of HSR significantly attenuated endotoxemia-induced histological changes, inhibited hepatic NF-kappaB activation and IkappaBalpha degradation and decreased mortality. Expression of mRNA coding for TNF-alpha and IL-6 in liver was significantly lower in arsenite-pretreated animals. We conclude that attenuation of endotoxin-induced hepatic NF-kappaB activation and subsequent proinflammatory cytokine production may be one of the mechanisms of the beneficial effect of the heat shock response.


One-pot cycloisomerization/hetero-Diels-Alder reaction of 1,6-enynes with aldehydes catalyzed by rhodium and a Brønsted acid.
A rhodium and Brønsted acid catalyzed one-pot cycloisomerization/hetero-Diels-Alder reaction of 1,6-enynes with unactivated aldehydes was established under mild conditions. This one-pot catalytic protocol produced a wide variety of annulated dihydropyrans from readily available starting materials in a highly atom economical manner.


Characterization and Validation of Canine P-Glycoprotein-Deficient MDCK II Cell Lines for Efflux Substrate Screening.
We characterized three canine P-gp (cP-gp) deficient MDCKII cell lines. Their relevance for identifying efflux transporter substrates and predicting limitation of brain penetration were evaluated. In addition, we discuss how compound selection can be done in drug discovery by using these cell systems. hMDR1, hBCRP-transfected, and non-transfected MDCKII ZFN cells (all with knock-down of endogenous cP-gp) were used for measuring permeability and efflux ratios for substrates. The compounds were also tested in MDR1_Caco-2 and BCRP_Caco-2, each with a double knock-out of BCRP/MRP2 or MDR1/MRP2 transporters respectively. Efflux results were compared between the MDCK and Caco-2 models. Furthermore, in vitro MDR1_ZFN efflux data were correlated with in vivo unbound drug brain-to-plasma partition coefficient (Kp,uu). MDR1 and BCRP substrates are correctly classified and robust transporter affinities with control substrates are shown. Cell passage mildly influenced mRNA levels of transfected transporters, but the transporter activity was proven stable for several years. The MDCK and Caco-2 models were in high consensus classifying same efflux substrates. Approx. 80% of enlisted substances were correctly predicted with the MDR1_ZFN model for brain penetration. cP-gp deficient MDCKII ZFN models are reliable tools to identify MDR1 and BCRP substrates and useful for predicting efflux liability for brain penetration.


Tumour budding in colorectal cancer: what do we know and what can we do?
Budding is a process during which individual or small clusters of up to five tumour cells detach from the main tumour mass and invade into the surrounding stroma. In colorectal cancer, this feature is observed in 20-40% of cases and is associated with lymphovascular invasion, lymph node and distant metastases, and poor prognosis. A variety of scoring systems for budding have been proposed but so far a gold standard is lacking, hampering implementation of a budding score in guidelines for pathological examination of colorectal cancer. Furthermore, little is known about the mechanisms which cause tumour cells to detach from the main tumour mass and obtain increased invasive potential. In this review, we present an overview of tumour budding including its definition, scoring systems, prognostic relevance and biological mechanisms involved.


Tie me up, tie me down: inhibiting RNA polymerase.
Mechanistic understanding of antibiotic action can yield crucial insights that aid in the design of new antibiotics. In this issue, Mukhopadhyay et al. (2008) uncover the mechanism by which the antibiotic myxopyronin inhibits bacterial RNA polymerase, suggesting a new target region in RNA polymerase for inhibitor design.


Approaches to advance drug discovery for neglected tropical diseases.
Neglected tropical diseases (NTDs), which include leishmaniasis, Chagas disease, human African trypanosomiasis (HAT), and schistosomiasis, remain public health problems in developing countries, as highlighted in the 2021-2030 WHO Roadmap on NTDs. This agenda sets the challenges for the control and elimination of NTDs by 2030. Fortunately, NTD drug discovery has shifted from traditional to modern strategies combining medicinal chemistry, phenotypic and molecular assays, multiparameter optimization, structural biology, and omics approaches. Structure- and ligand-based drug design have fostered NTD drug discovery by enabling data-driven molecular optimization, expansion to previously inaccessible chemical spaces, and knowledge building from biological data. These efforts have integrated parasite biology and medicinal chemistry to advance drug discovery in this key area of global health.


CHARGE syndrome. Part I. External ear anomalies.
Ear anomalies and hearing loss are major components of CHARGE Syndrome. This paper describes the external ear anomalies found in this syndrome: short wide pinnae, often cupped and asymmetrical; distinctive triangular concha; discontinuity between the antihelix and antitragus; and 'snipped-off' portions of the helical folds. The patterns of anomalies are so distinctive that a preliminary diagnosis of CHARGE Syndrome can often be made on the basis of ear shape alone. Part II of this communication describes hearing loss in this syndrome.


A simple integrated system for rapid analysis of sialic-acid-containing N-glycopeptides from human serum.
Terminal sialylation is very important in cancer biology and has been extensively investigated for the discovery of potential clinical biomarkers of cancers. In this study, we presented a novel approach, by using of Ti(IV)-IMAC, to enrich sialic-acid-containing N-glycopeptides for the analysis of terminal sialylation. Compared with conventional method using TiO2 , this approach obtained 2.5 times more glycopeptides and glycosylation sites. Then, a simple integrated system combining filter-aided sample preparation, ACN-improved digestion, and Ti(IV)-IMAC enrichment was established for efficient analysis. In this system, protein digestion, glycopeptide enrichment, and deglycosylation were integrated and were performed sequentially in a single filter unit without any need for desalting, lyophilization, or sample transfer procedures. As a result, the number of identifications was improved by 1.5-fold and the total processing time was drastically reduced to only 7-8 h. By using this system, fast and efficient analysis of human serum sialylated N-glycoproteome was achieved. From only 1 μL of human serum, 217 unique glycopeptides and 194 glycosylation sites were successfully identified.


Neighborhood characteristics as confounders and effect modifiers for the association between air pollution exposure and subjective cognitive functioning.
Air pollution has been associated with cognitive function in the elderly. Previous studies have not evaluated the simultaneous effect of neighborhood-level socioeconomic status (N-SES), which can be an essential source of bias. We explored N-SES as a confounder and effect modifier in a cross-sectional study of air pollution and subjective cognitive function. We included 12,058 participants age 50+ years from the Emory Healthy Aging Study in Metro Atlanta using the Cognitive Function Instrument (CFI) score as our outcome, with higher scores representing worse subjective cognitive function. We estimated 9-year average ambient carbon monoxide (CO), nitrogen oxides (NOx), and fine particulate matter (PM2.5) concentrations at residential addresses using a fusion of dispersion and chemical transport models. We collected census-tract level N-SES indicators and created two composite measures via principal component analysis and k-means clustering. Associations between pollutants and CFI and effect modification by N-SES were estimated via linear regression models adjusted for age, education, race and N-SES. N-SES confounded the association between air pollution and CFI, independent of individual characteristics. We found significant effect modifications by N-SES for the association between air pollution and CFI (p-values<0.001) suggesting that effects of air pollution differ depending on N-SES. Participants living in areas with low N-SES were most vulnerable to air pollution. In the lowest N-SES urban areas, interquartile range (IQR) increases in CO, NOx, and PM2.5 were associated with 5.4% (95%-confidence interval, -0.2,11.3), 4.9% (-0.4,10.4), and 9.8% (2.2,18.0) changes in CFI, respectively. In lowest N-SES suburban areas, IQR increases in CO, NOx, and PM2.5 were associated with higher changes in CFI, namely 13.0% (0.9,26.5), 13.0% (-0.1,27.8), and 17.3% (2.5,34.2), respectively. N-SES is an important confounder and effect modifier in our study. This finding could have implications for studying health effects of air pollution and identifying susceptible populations.


Metabolomics insight into the influence of environmental factors in responses of freshwater biofilms to the model herbicide diuron.
Freshwater biofilms have been increasingly used during the last decade in ecotoxicology due to their ecological relevance to assess the effect(s) of environmental stress at the community level. Despite growing knowledge about the effect of various stressors on the structure and the function of these microbial communities, a strong research effort is still required to better understand their response to chemical stress and the influence of environmental stressors in this response. To tackle this challenge, untargeted metabolomics is an approach of choice because of its capacity to give an integrative picture of the exposure to multiple stress and associated effect as well as identifying the molecular pathways involved in these responses. In this context, the present study aimed to explore the use of an untargeted metabolomics approach to unravel at the molecular/biochemical level the response of the whole biofilm to chemical stress and the influence of various environmental factors in this response. To this end, archived high-resolution mass spectrometry data from previous experiments at our laboratory on the effect of the model photosynthesis inhibitor diuron on freshwater biofilm were investigated by using innovative solutions for OMICs data (e.g., DRomics) and more usual chemometric approaches (multivariate and univariate statistical analyses). The results showed a faster (1 min) and more sensitive response of the metabolome to diuron than usual functional descriptors, including photosynthesis. Also, the metabolomics response to diuron resulted from metabolites following various trends (increasing, decreasing, U/bell shape) along increasing concentration and time. This metabolomics response was influenced by the temperature, photoperiod, and flow. A focus on a plant-specific omega-3 (eicosapentaenoic acid) playing a key role in the trophic chain highlighted the potential relevance of metabolomics approach to establish the link between molecular alteration and ecosystem structure/functioning impairment but also how complex is the response and the influence of all the tested factors on this response at the metabolomics level. Altogether, our results underline that more fundamental researches are needed to decipher the metabolomics response of freshwater biofilm to chemical stress and its link with physiological, structural, and functional responses toward the unraveling of adverse outcome pathways (AOP) for key ecosystem functions (e.g., primary production).


Prolonged P-Wave and QT Dispersion in Children with Inflammatory Bowel Disease in Remission.
Objectives. Ulcerative colitis (UC) and Crohn's disease (CD) are chronic inflammatory bowel diseases (IBD) with unclear underlying aetiologies. Severe cardiac arrhythmias have been emphasised in a few studies on adult IBD patients. This study aimed to investigate the alteration of the P-wave and QT interval dispersion parameters to assess the risk of atrial conduction and ventricular repolarisation abnormalities in pediatric IBD patients. Patients and Methods. Thirty-six IBD patients in remission (UC: 20, CD: 16) aged 3-18 years and 36 age- and sex-matched control patients were enrolled in the study. Twelve-lead electrocardiograms were used to determine durations of P-wave, QT, and corrected QT (QTc) interval dispersion. Transthoracic echocardiograms and 24-hour rhythm Holter recordings were obtained for both groups. Results. The P-wave dispersion, QT dispersion, and QTc interval dispersion (Pdisp, QTdisp, and QTcdisp) were significantly longer in the patient group. The mean values of Pminimum, Pmaximum, and QTcminimum were significantly different between the two groups. The echocardiography and Holter monitoring results were not significantly different between the groups. Furthermore, no differences in these parameters were detected between the CD and UC groups. Conclusion. Results suggest that paediatric IBD patients may carry potential risks for serious atrial and ventricular arrhythmias over time even during remission.


Lipid modulation of membrane-bound epitope recognition and blocking by HIV-1 neutralizing antibodies.
The conserved, aromatic-rich membrane-proximal external region (MPER) of gp41 is functional in human immunodeficiency virus (HIV)-cell fusion by perturbing membrane integrity. Broadly-neutralizing 2F5 and 4E10 monoclonal antibodies (MAb-s) recognize amino- and carboxy-terminal epitope sequences within this domain, respectively. An MPER peptide overlapping 2F5 and 4E10 epitope sequences was capable of breaching the permeability barrier of lipid vesicles. Cholesterol and sphingomyelin raft-lipids, present at high quantities in the HIV-1 envelope, promoted exposure or occlusion of 4E10 epitope, respectively. Conversely, 2F5 epitope accessibility was affected to a lesser extent by these envelope lipids. These observations support the idea that MPER epitopes on membranes are segmented in terms of how they are affected by envelope lipids, which may have implications for MPER-based vaccine development.


Sentinel surveillance of substance-related self-harm in Canadian emergency departments, 2011 - 19.
Self-harm is a public health concern that can result in serious injury or death. This study provides an overview of emergency department (ED) visits for patients presenting with substance-related self-harm. Cases of self-harm in the electronic Canadian Hospitals Injury Reporting and Prevention Program (eCHIRPP) database were extracted (April 2011 to September 2019; N = 15,682), using various search strategies to identify substance-related self-harm cases for patients 10 years and older. Cases involving alcohol, cannabis, illicit drugs, or medications (or any combinations of these) were included. Additional variables, including age and sex, location and the severity of injury (hospital admission) were examined. Proportionate injury ratios (PIR) were used to compare emergency department outcomes of self-harm and unintentional injuries involving substance use. Time trends were quantified using Joinpoint regression. For cases requiring hospital admission, text fields were analyzed for contextual factors. A total of 9470 substance-related self-harm cases were reported (28.1% of all intentional injury cases), representing 820.0 records per 100,000 eCHIRPP records. While age patterns for both sexes were similar, the number of cases for females was significantly higher among 15-19 year olds. Over half (55%) of cases that identified substance type involved medications, followed by multi-type substance use (19.8%). In the ED, there were proportionally more treatments, observations, and admissions presenting with substance-related self-harm compared to substance-related unintentional injury cases. Among those aged 20+ years, a statistically significant increasing trend of 15.9% per year was observed, while among those aged 10-19 years a significant annual percent change of 16.9% was noted (2011 to 2019). Text field analysis demonstrated suicide attempt or ideation was a reoccurring theme among all age groups. Poor mental health status or conflict with family or an intimate partner were reported stressors, depending on age group. Additional self-harming injuries, such as cutting, were reported among all age groups. Our study found that hospital admission for substance-related self-harm was highest for patients aged 15-19 years, especially females, and that they were more likely to use medications. The statistically significant increasing trend of cases found between 2011 and 2019 is notable. Patients showed multiple types of adversities, demonstrating the complexity of this issue.


Non-invasive assessment of cirrhosis using multiphasic dual-energy CT iodine maps: correlation with model for end-stage liver disease score.
To determine whether multiphasic dual-energy (DE) CT iodine quantitation correlates with the severity of chronic liver disease. We retrospectively included 40 cirrhotic and 28 non-cirrhotic patients who underwent a multiphasic liver protocol DECT. All three phases (arterial, portal venous (PVP), and equilibrium) were performed in DE mode. Iodine (I) values (mg I/ml) were obtained by placing regions of interest in the liver, aorta, common hepatic artery, and portal vein (PV). Iodine slopes (λ) were calculated as follows: (Iequilibrium-Iarterial)/time and (Iequilibrium-IPVP)/time. Spearman correlations between λ and MELD scores were evaluated, and the area under the curve of the receiver operating characteristic (AUROC) was calculated to distinguish cirrhotic and non-cirrhotic patients. Cirrhotic and non-cirrhotic patients had significantly different λequilibrium-arterial [IQR] for the caudate (λ = 2.08 [1.39-2.98] vs 1.46 [0.76-1.93], P = 0.007), left (λ = 2.05 [1.50-2.76] vs 1.51 [0.59-1.90], P = 0.002) and right lobes (λ = 1.72 [1.12-2.50] vs 1.13 [0.41-0.43], P = 0.003) and for the PV (λ = 3.15 [2.20-5.00] vs 2.29 [0.85-2.71], P = 0.001). λequilibrium-PVP were significantly different for the right (λ = 0.11 [- 0.45-1.03] vs - 0.44 [- 0.83-0.12], P = 0.045) and left lobe (λ = 0.30 [- 0.25-0.98] vs - 0.10 [- 0.35-0.24], P = 0.001). Significant positive correlations were found between MELD scores and λequilibrium-arterial for the caudate lobe (ρ = 0.34, P = 0.004) and λequilibrium-PVP for the caudate (ρ = 0.26, P = 0.028) and right lobe (ρ = 0.33, P = 0.007). AUROC in distinguishing cirrhotic and non-cirrhotic patients were 0.72 (P = 0.002), 0.71 (P = 0.003), and 0.75 (P = 0.001) using λequilibrium-arterial for the left lobe, right lobe, and PV, respectively. The λequilibrium-PVP AUROC of the right lobe was 0.73 (P = 0.001). Multiphasic DECT iodine quantitation over time is significantly different between cirrhotic and non-cirrhotic patients, correlates with the MELD score, and it could potentially serve as a non-invasive measure of cirrhosis and disease severity with acceptable diagnostic accuracy.


Synthesis of aminoacyl adenylates and their role in abiogenic peptide synthesis.
Preparative synthesis of adenylates of amino acids with modifications of Meister's method, pertaining to the purification and identification of the reaction products, is described. The significance of the synthesized substances is discussed in connection with the problem of abiogenic synthesis of peptides.


The sense of agency shapes body schema and peripersonal space.
Body schema, a sensorimotor representation of the body used for planning and executing movements, is plastic because it extends by using a tool to reach far objects. Modifications of peripersonal space, i.e., a functional representation of reach space, usually co-occur with body schema changes. Here, we hypothesized that such plastic changes depend on the experience of controlling the course of events in space trough one's own actions, i.e., the sense of agency. In two experiments, body schema and peripersonal space were assessed before and after the participants' sense of agency over a virtual hand was manipulated. Body schema and peripersonal space enlarged or contracted depending on whether the virtual hand was presented in far space, or closer to the participants' body than the real hand. These findings suggest that body schema and peripersonal space are affected by the dynamic mapping between intentional body movements and expected consequences in space.


Fast variable density Poisson-disc sample generation with directional variation for compressed sensing in MRI.
We present a fast method for generating random samples according to a variable density poisson-disc distribution. A minimum parameter value is used to create a background grid array for keeping track of those points that might affect any new candidate point; this reduces the number of conflicts that must be checked before acceptance of a new point, thus reducing the number of computations required. We demonstrate the algorithm's ability to generate variable density poisson-disc sampling patterns according to a parameterized function, including patterns where the variations in density are a function of direction. We further show that these sampling patterns are appropriate for compressed sensing applications. Finally, we present a method to generate patterns with a specific acceleration rate.


Visible-Light-Switchable Tellurium-Based Chalcogen Bonding: Photocontrolled Anion Binding and Anion Abstraction Catalysis.
Exploring new noncovalent bonding motifs with reversibly tunable binding affinity is of fundamental importance in manipulating the properties and functions of supramolecular self-assembly systems and materials. Herein, for the first time, we demonstrate a unique visible-light-switchable telluro-triazole/triazolium-based chalcogen bonding (ChB) system in which the Te moieties are connected by azobenzene cores. The binding strengths between these azo-derived ChB receptors and the halide anions (Cl- , Br- ) could be reversibly regulated upon irradiation by visible light of different wavelengths. The cis-bidentate ChB receptors exhibit enhanced halide anion binding ability compared to the trans-monodentate receptors. In particular, the telluro-triazolium-based ChB receptor can achieve both high and significantly photoswitchable binding affinities for halide anions, which enable it to serve as an efficient photocontrolled organocatalyst for ChB-assisted halide abstraction in a Friedel-Crafts alkylation benchmark reaction.


Distribution of input and output synapses on the central branches of bushcricket and cricket auditory afferent neurones: immunocytochemical evidence for GABA and glutamate in different populations of presynaptic boutons.
In order to investigate the synapses on the terminals of primary auditory afferents in the bushcricket and cricket, these were impaled with microelectrodes and after physiological characterisation, injected intracellularly with horseradish peroxidase. The tissue was prepared for electron microscopy, and immunocytochemistry for gamma-aminobutyric acid (GABA) and glutamate was carried out on ultrathin sections by using a post-embedding immunogold technique. The afferent terminals received many input synapses. Between 60-65% of these were made by processes immunoreactive for GABA and approximately 25% from processes immunoreactive for glutamate. The relative distribution of the different classes of input were analysed from serial section reconstruction of terminal afferent branches. Inputs from GABA and glutamate-immunoreactive processes appeared to be scattered at random over the terminal arborisation of the afferents both with respect to each other and to the architecture of the terminals. They were, however, always found close to the output synapses. The possible roles of presynaptic inhibition in the auditory afferents is discussed in the context of the auditory responses of the animals.


Neonatal mortality in Jordan: secondary analysis of Jordan Population and Family Health Survey (JPFHS) data.
This study aimed to analyze the 2009 Jordan Population and Family Health Survey (JPFHS) data to determine the level, trend, and distribution of neonatal mortality (NNM) in Jordan and determine its associated factors. Nationally representative data on NNM were extracted from the JPFHS data. Using multivariate analyses, the strength of associations between 12 clinical/sociodemographic variables and neonatal mortality were quantified after controlling for potential confounders. The weighted NNM rate for 2005-2009 period was 16 deaths per 1000 live births, with the early NNM rate and late NNM rates were 10 deaths per 1000 live births and six deaths per 1000 live births, respectively. Fluctuations of NNM according to year of birth and geographic variations were noted. Risk of NNM increased among male newborns, as mother's education level decreased, in mothers 40-49 years old, in multiple gestations-low birth weight neonates, and as birth interval was <3 years. The NNR rate for 2005-2009 period of 16 deaths per 1000 live births indicates that there are opportunities to decrease it. Risk factors of neonatal mortality with respect to predictors of death during first days of life and variables related to geographic variations require particular focus to improve the quality of obstetric and neonatal health services and to decrease neonatal mortality.


A simple breathing circuit allowing precise control of inspiratory gases for experimental respiratory manipulations.
Respiratory manipulations modulating blood flow and oxygenation levels have become an important component of modern functional MRI applications. Manipulations often consist of temporarily switching inspired fractions of CO2 and O2; and have typically been performed using simple oxygen masks intended for applications in respiratory therapy. However, precise control of inspired gas composition is difficult using this type of mask due to entrainment of room air and resultant dilution of inspired gases. We aimed at developing a gas delivery apparatus allowing improved control over the fractional concentration of inspired gases, to be used in brain fMRI studies. The breathing circuit we have conceived allowed well controlled step changes in FiO2 and FiCO2, at moderate flow rates achievable on standard clinical flow regulators. In a two run test inside the scanner we demonstrate that tightly controlled simple gas switching manipulations can afford good intra-subject reproducibility of induced hyperoxia/hypercapnia responses. Although our approach requires a non-vented mask fitting closely to the subject's face, the circuit ensures a continuous supply of breathable air even if the supply of medical gases is interrupted, and is easily removable in case of an emergency. The apparatus we propose is also compact and MRI compatible, allowing subject placement in confined spaces such as an MRI scanner for brain examinations. We have reported a new approach for the controlled administration of medical gases, and describe an implementation of the breathing circuit that is MRI compatible and uses commercially available parts. The resultant apparatus allows simple, safe and precise manipulations of FiO2 and FiCO2.


Can usual gait speed be used as a prognostic factor for early palliative care identification in hospitalized older patients? A prospective study on two different wards.
Timely palliative care in frail older persons remains challenging. Scales to identify older patients at risk of functional decline already exist. However, factors to predict short term mortality in older hospitalized patients are scarce. In this prospective study, we recruited patients of 75 years and older at the department of cardiology and geriatrics. The usual gait speed measurement closest to discharge was chosen. We used the risk of dying within 1 year as parameter for starting palliative care. ROC curves were used to determine the best cut-off value of usual gait speed to predict one-year mortality. Time to event analyses were assessed by COX regression. On the acute geriatric ward (n = 60), patients were older and more frail (assessed by Katz and iADL) in comparison to patients on the cardiology ward (n = 82); one-year mortality was respectively 27 and 15% (p = 0.069). AUC on the acute geriatric ward was 0.748 (p = 0.006). The best cut-off value was 0.42 m/s with a sensitivity and specificity of 0.857 and 0.643. Slow walkers died earlier than faster walkers (HR 7.456, p = 0.011), after correction for age and sex. On the cardiology ward, AUC was 0.560 (p = 0.563); no significant association was found between usual gait speed and survival time. Usual gait speed may be a valuable prognostic factor to identify patients at risk for one-year mortality on the acute geriatric ward but not on the cardiology ward.


Facilitation of retention performance in mice by pretest microinjection of AVP into dorsal or ventral hippocampus: differential influence of the peptide on appetitive task.
Pre-test local microinjection of arginine-vasopressin (AVP) into dorsal or ventral hippocampus resulted in an improvement of retention performance in an appetitively motivated task. Nevertheless, a better improvement appeared when AVP treatment was performed into ventral hippocampus suggesting a higher sensitivity of this part of hippocampus to the action of AVP. To examine a non-specific behavioral action of the peptide, the effect of AVP treatment on locomotor activity was assessed. When the treatment was given into ventral hippocampus, a reduction of locomotor activity was recorded, whereas after AVP injection into dorsal hippocampus, the peptide failed to alter locomotor activity.


Transcription factor TCF-1 regulates the functions, but not the development, of lymphoid tissue inducer subsets in different tissues.
Lymphoid tissue inducer (LTi) cells, a subset of innate lymphoid cells (ILCs), play an essential role in the formation of secondary lymphoid tissues. However, the regulation of the development and functions of this ILC subset is still elusive. In this study, we report that the transcription factor T cell factor 1 (TCF-1), just as GATA3, is indispensable for the development of non-LTi ILC subsets. While LTi cells are still present in TCF-1-deficient mice, the organogenesis of Peyer's patches (PPs), but not of lymph nodes, is impaired in these mice. LTi cells from different tissues have distinct gene expression patterns, and TCF-1 regulates the expression of lymphotoxin specifically in PP LTi cells. Mechanistically, TCF-1 may directly and/or indirectly regulate Lta, including through promoting the expression of GATA3. Thus, the TCF-1-GATA3 axis, which plays an important role during T cell development, also critically regulates the development of non-LTi cells and tissue-specific functions of LTi cells.


The items in the Chinese version of the Montreal cognitive assessment basic discriminate among different severities of Alzheimer's disease.
To determine whether items of the Chinese version of the Montreal Cognitive Assessment Basic (MoCA-BC) could discriminate among cognitively normal controls (NC), and those with mild cognitive impairment (MCI), mild Alzheimer's disease (AD), and moderate-severe (AD), as well as their sensitivity and specificity. MCI (n = 456), mild AD (n = 502) and moderate-severe AD (n = 102) patients were recruited from the memory clinic, Huashan Hospital, Shanghai, China. NC (n = 329) were recruited from health checkup outpatients. Five MoCA-BC item scores were collected in interviews. The MoCA-BC orientation test had high sensitivity and specificity for discrimination among MCI, mild AD and moderate-severe AD. The delayed recall memory test had high sensitivity and specificity for MCI screening. The verbal fluency test was efficient for detecting MCI and differentiating AD severity. Various items of the MoCA-BC can identify MCI patients early and identify the severity of dementia.


Aqua-bis-(4-fluoro-benzoato-κO)bis-(nicotinamide-κN)copper(II) nicotinamide hemisolvate trihydrate.
The asymmetric unit of the title compound, [Cu(C(7)H(4)FO(2))(2)(C(6)H(6)N(2)O)(2)(H(2)O)]·0.5C(6)H(6)N(2)O·3H(2)O, contains two aqua-bis-(4-fluoro-benzoato)bis-(nicotinamide)-copper(II) mol-ecules, one nicotinamide solvent mol-ecule and six water mol-ecules. The Cu(II) ion is coordinated by two O atoms from two 4-fluoro-benzoate ligands, two N atoms from two nicotinamide ligands and one water O atom in a distorted square-pyramidal geometry. In the crystal, O-H⋯O, O-H⋯N and N-H⋯O hydrogen bonds consolidate the crystal packing, which also exhibits π-π inter-actions between the aromatic rings [centroid-centroid distances 3.692 (2)-3.794 (2) Å].


Alterations in the Ca2+ sensitivity of tension development by single skeletal muscle fibers at stretched lengths.
The apparent length dependence in the calcium sensitivity of tension development in skeletal muscle has been investigated in the present study. At sarcomere lengths of 2.46-2.62 micron, the Hill plot of tension-pCa data is well fit by not one but two straight lines, suggesting the possible involvement of more than a single class of Ca2+-binding site in tension development. On the other hand, increasing the sarcomere length to 3.00-3.25 micron yielded Hill plots that were described by a single straight line, which indicates that at long lengths tension might be regulated by the binding of Ca2+ to a single class of Ca2+-binding sites, presumably the low affinity sites of TnC. This length-dependent transformation of the tension pCa relation occurred at free Mg2+ concentrations of both 0.05 and 3.2 mM. Although the mechanism of this effect is uncertain, plausible explanations for the biphasic Hill plot at the shorter lengths include the possible involvement of Ca2+ activation of the thick filaments and/or myosin LC2 phosphorylation in the process of tension development.


Prothymosin alpha is not a nuclear polypeptide.
Using a radioimmunoassay for the NH2-terminus of prothymosin alpha, the crossreactive material was measured in subcellular fractions of calf thymus and liver. No significant amount of crossreactive material was found in the nucleus. This provides experimental evidence against a recent hypothesis, based on structural evidence, that prothymosin alpha is a nuclear polypeptide.


Formation of a Double Diamond Cubic Phase by Thermotropic Liquid Crystalline Self-Assembly of Bundled Bolaamphiphiles.
A quaternary amphiphile with swallow-tail side groups displays a new bicontinuous thermotropic cubic phase with symmetry Pn3‾ m and formed by two interpenetrating networks where cylindrical segments are linked by H bonds at tetrahedral junctions. Each network segment contains two bundles, each containing 12 rod-like mesogens, lying along the segment axis. This assembly leads to the first thermotropic structure of the "double diamond" type. A quantitative geometric model is proposed to explain the occurrence of this rare phase.


Optoelectronic refractometric sensing device for gases based on dielectric bow-ties and amorphous silicon solar cells.
The transformation of an hydrogenated amorphous silicon solar cell (aSiH) into an optoelectronic refratometric sensor has been possible through the addition of dielectric bow-tie resonant structures. The indium transparent oxide top electrode is replaced by a thin metallic layer to selectively prevent the direct transmission of light to the active layer of the cell. Then, an array of dielectric bow-tie structures is placed on top of this electrode, to activate the optical absorption through surface plasmon resonance (SPR). The whole device is exposed to the analyte under measure, which is the surrounding medium. Three different dielectric materials with low, medium, and high refractive index were selected for the bow-ties, namely magnesium fluoride (MgF[Formula: see text]), silicon dioxide (SiO[Formula: see text]), and aluminum nitride (AlN) have been tested as coupling structure for SPR excitation. The maximization of the readout/short circuit current has been achieved through the geometrical parameters of such structure. We have selected the geometrical parameters to maximize the short circuit current delivered by the a-Si cell at a given selected wavelength. The design has been customized to gas measurements application, where the index of refraction is slightly above 1 around 10[Formula: see text]. Our analysis reveals ultra-high sensitivity of [Formula: see text] (mA/W)/RIU, and a figure of merit FOM= 107 RIU[Formula: see text], when the bow-tie is made of SiO[Formula: see text]. A performance rally competitive with those previously reported in literature, with the additional advantage of circunventing both moving parts and spectral interrogation elements.


Separate activation sites for cholecystokinin and bombesin on pancreatic acini: an electrophysiological study employing a competitive antagonist for the action of CCK.
The effects of dibutyryl cyclic guanosine 3':5' monophosphate (dbcGMP) on the electrical responses of in vitro mouse pancreatic acinar cells to caerulein, bombesin and acetylcholine, applied by microionophoresis, were investigated using intracellular microelectrode recordings. Exposure to dbcGMP (10(-3) mol . 1-1) quickly abolished the depolarization response to caerulein ionophoresis, while the bombesin-nonapeptide and acetylcholine-induced depolarizations were retained. Exposing acinar cells to 2 x 10(-4) mol . 1-1 dbcGMP reduced their sensitivity such that a 10-fold increase in the applied caerulein ionophoresis current was required to restore the responses to the same magnitude as those obtained in a dbcGMP-free environment. The response to topical applications of pentagastrin and CCK-33 were also abolished by dbcGMP. The results provide direct evidence that functional ACh, bombesin and CCK receptors are all present within the same acinar cell unit. The dbcGMP-induced inhibition of responses evoked by CCK-like peptides is immediate, specific and easily reversible. DbcGMP acts as a competitive antagonist of the CCK receptor on pancreatic acinar cells.


Clinical phenotype of schizophrenia in a Finnish isolate.
We identified all cases in Finland (population of 5 million) with a diagnosis of schizophrenia born between 1940 and 1969, using four national computerised registers with high reliability. A sample of 397 families was identified in a genetically homogeneous internal isolate (population of 18,000) in northeastern Finland with high prevalence for schizophrenia and an LOD score of 3.8 in chromosome 1. Our aim was to examine with Operational Criteria Checklist for Psychotic Illness (OCCPI) factor analysis the psychotic and affective signs and symptoms of schizophrenia in this genetically homogeneous population, and compare them with findings from individuals with schizophrenia from multiplex families from the whole country. After collecting all original case notes, we made DSM-IV consensus diagnoses and completed OCCPI ratings on a lifetime basis. For the factor analysis, we accepted 190 patients with a diagnosis of schizophrenia. In addition, 466 schizophrenia patients from 147 multiplex families from the whole country were included in the analysis. The OCCPI factor analysis resulted in four factors: "delusions and hallucinations" and "negative" factors, plus two affective ("manic" and "depressive") factors. We compared the pattern of symptoms among three patient groups: isolate patients who were the only affected individuals in their family, isolate patients who had affected family members, and patients from the whole country with affected family members. We found no clear differences among these groups. However, there were significant differences in the frequency of individual OCCPI items between the study groups. Findings in this schizophrenia OCCPI phenotype study suggest that the clinical picture of schizophrenia in a genetically isolated and homogeneous population closely resembles our nationwide findings in Finland.


Differentiation of Hebbian and homeostatic plasticity mechanisms within layer 5 visual cortex neurons.
Cortical layer 5 contains two major types of projection neuron known as IB (intrinsic bursting) cells that project sub-cortically and RS (regular spiking) cells that project between cortical areas. This study describes the plasticity properties of RS and IB cells in the mouse visual cortex during the critical period for ocular dominance plasticity. We find that RS neurons exhibit synaptic depression in response to both dark exposure (DE) and monocular deprivation (MD), and their homeostatic recovery from depression is dependent on TNF-α. In contrast, IB cells demonstrate opposite responses to DE and MD, potentiating to DE and depressing to MD. IB cells' potentiation depends on CaMKII-autophosphorylation and not TNF-α. IB cells show mature synaptic properties at the start of the critical period while RS cells mature during the critical period. Together with observations in somatosensory cortex, these results suggest that differences in RS and IB plasticity mechanisms are a general cortical property.


Hippocampal sclerosis and status epilepticus: cause or consequence? A MRI study.
Transient imaging abnormalities, including changes on diffusion-weighted imaging (DWI), may be seen in status epilepticus. These abnormalities can be followed by hippocampal sclerosis. We report a 15-year-old lady with focal non convulsive status epilepticus (NCSE) and focal slowing on EEG. DWI exhibited abnormal hyperintense signals in bilateral temporal and insular cortices. After 3 weeks, MRI performed a localizated hippocampal atrophy. The MRI findings indicated vasogenic and cytotoxic edema during seizure activity and subsequent loss of brain parenchyma.


Short-term Outcome of Single-Anastomosis Plication Ileal Bypass (SAPI) in Treatment of Morbid Obesity.
This prospective study aimed to report the short-term outcome of the single-anastomosis plication ileal (SAPI) bypass in the treatment of morbid obesity. Adult patients with morbid obesity who underwent SAPI procedure were recruited to this prospective study. SAPI procedure involved plication of the greater curvature of the stomach in two rows then performing a stapled side-to-side anastomosis between an ileal loop and the gastric antrum. Body mass index (BMI), percentage excess weight loss (%EWL), percentage total weight loss (%TWL), and improvement in comorbidities were recorded at 6 and 12 months postoperatively. The present study included 56 patients (48 female) of a mean age of 37.3 years. There was a significant decrease in BMI at 6 months (37.2 ± 9.3) and 12 months (31.5 ± 7.8) as compared with the baseline BMI (47.9 ± 5.7). The %EWL at 12 months was 72.5 ± 16.2, significantly higher than its value at 6 months (50.1 ± 15.6). The %TWL at 12 months was 36.4 ± 6.4, significantly higher than its value at 6 months (24.9 ± 6.3). All patients with DM showed remission or improvement in their diabetic state. Improvement in hyperlipidemia and hypertension was recorded in 81.8% and 77.8% of patients, respectively. Postoperative complications were recorded in five (8.9%) patients. SAPI procedure achieved significant reduction in body weight and BMI, significant %EWL, and satisfactory improvement in comorbidities at 12 months after surgery. Longer follow-up of patients is needed to reach more solid conclusions on the efficacy and safety of this new technique.


Impact of educational intervention on the knowledge, attitude, and practice of pharmacovigilance among postgraduates of a tertiary care center, Kanchipuram, Tamil Nadu, India.
Prescription of drugs should always be done in a judicious manner and with a satisfactory risk/benefit ratio. Pharmacotherapeutic agents are one of the important causes of adverse effects starting from mere inconvenience to permanent disability and death. Studies suggest that about 0.2%-24% of patients with adverse drug reactions (ADRs) are subjected to hospital admission in India as well as in several highly developed industrialized countries. India contributes below 1% in terms of ADR reporting against the world rate of 5%. To enhance the reporting rate, it is important to improve the knowledge, attitude, and practice (KAP) of all the health-care professionals with regard to the ADR reporting and the pharmacovigilance (PV). The aim of the study was to evaluate the basic KAP of the postgraduate (PG) students at Meenakshi Medical College and Hospital, Enathur, Kanchipuram, Tamilnadu, India, regarding ADR monitoring and PV. This was a before and after comparison study with an educational intervention. A knowledge-, attitude-, and practice-based questionnaire on ADR reporting and PV program was prepared and administrated. Participants had good theoretical knowledge regarding PV, but their attitudes and practical knowledge increased significantly after an educational intervention. The overall scores observed between pretest and posttest were found to be statistically significant. Educational intervention had proven to be an effective tool in improving the KAP of PV in the present study. Lack of motivation and training toward ADR reporting discourages PGs from reporting. Revisions are needed to include the clinical application of PV in the present academic curriculum. Ensuring a better safety profile for drugs can be done only through PV.


Evaluation of Stromal Myofibroblasts in Laryngeal Dysplasia and Invasive Squamous Cell Carcinoma.
Malignant tumors consist of both carcinoma cells and tumor associated host cells. Host cells has started to receive more attention regarding their role in tumor progression such as invasion and metastasis. Fibroblasts that are incorporated in the tumoral stroma are called as peritumoral fibroblasts, reactive stroma, cancer-related fibroblasts or myofibroblasts. In general fibroblasts next to nich of cancer cells express alpha-smooth muscle actin (α-SMA) which is an important marker for differentiated myofibroblasts. Our aim is to investigate the role of α-SMA positive myofibroblasts in the development and progression of laryngeal carcinoma. The proportion of α-SMA positive myofibroblasts are scored from (1 +) to 3( +) in laryngeal dysplasia (n = 17) and microinvasive and invasive squamous cell carcinoma (n = 66). α-SMA expression in invasive carcinoma and dysplasia was analyzed statistically. No stromal myofibroblast was detected in mild dysplasia (score 0). Among 12 cases of moderate-severe dysplasia, in only 3 cases low α-SMA expression (score 1) was observed and in 9 cases there were no stromal myofibroblasts (score 0) were. In most cases of invasive carcinoma, high α-SMA expression (score 2, 3) was seen. α-SMA positive stromal myofibroblasts were significantly higher in invasive laryngeal squamous cell carcinoma compared to dysplasia (p < 0.05). Results of our study suggested that α-SMA positive stromal myofibroblasts play an important role in creating the permissive environment for tumor invasion in laryngeal squamous cell carcinoma. According to this data, we think that the presence of stromal myofibroblasts might be used as a helpful criterion in the differential diagnosis of true invasion and pseudoinvasion.


Antimitochondrial antibody-negative primary biliary cirrhosis.
Primary biliary cirrhosis (PBC) is considered a classic autoimmune disease insofar as 95% of patients are seropositive for specific antimitochondrial antibodies (AMA). Yet it is still the case that the remaining 5% of patients have equivalent disease but test persistently AMA negative. Although variations exist in the immunologic profile of these patients, clinically there are no discernable differences, and although the diagnostic threshold is higher, the treatment and prognosis mirror that of classic disease. Previous terminology, therefore, has been abandoned in favor of the description, AMA-negative PBC.


The effect of manipulations to target contrast on emmetropization in chick.
Emmetropization is dependent on visual feedback and presumably some measure of the optical and image quality of the eye. We investigated the effect of simple alterations to image contrast on eye growth and refractive development. A 1.6 cyc/deg square-wave-grating target was located at the end of a 3.3 cm cone, imaged by a +30 D lens and applied monocularly to the eyes of 8-day-old chicks. Eleven different contrast targets were tested: 95, 67, 47.5, 33.5, 24, 17, 12, 8.5, 4.2, 2.1, and 0%. Refractive error (RE), vitreous chamber depth (VC) and axial length (AL) varied with the contrast of the image (RE diff: F(10,86)=12.420, p<0.0005; VC diff: F(10,86)=8.756, p<0.0005; AL diff: F(10,86)=9.240, p<0.0005). Target contrasts 4.2% and lower produced relative myopia (4.2%: RE diff=-7.48+/-2.26 D, p=0.987; 2.1%: RE diff=-7.22+/-2.77 D, p=0.951) of similar amount to that observed in response to a featureless 0% contrast target (RE diff=-9.11+/-4.68 D). For target contrast levels 47.5% and greater isometropia was maintained (95%: RE diff =1.83+/-2.78 D; 67%: RE diff=0.14+/-1.84 D; 47.5%: RE diff=0.25+/-1.82 D). Contrasts in between produced an intermediate amount of myopia (33.5%: RE diff=-2.81+/-1.80 D; 24%: RE diff=-3.45+/-1.64 D; 17%: RE diff=-3.19+/-1.54 D; 12%: RE diff=-4.08+/-3.56 D; 8.5%: RE diff=-4.09+/-3.60 D). We conclude that image contrast provides important visual information for the eye growth control system or that contrast must reach a threshold value for some other emmetropization signal to function.


Studies of thyroglobulin autoantibody synthesis using a micro-ELISA assay.
Thyroglobulin autoantibody synthesis by Hashimoto lymphocyte cultures has been studied using an ELISA, a plaque assay and tanned red cell haemagglutination. The ELISA system was found to be the most suitable and using this method IgG-class thyroglobulin antibody synthesis was detectable in cultures of mitogen-stimulated lymphocytes from all 10 Hashimoto patients studied, but not in cultures of lymphocytes from 4 normal donors. The ELISA was also sufficiently sensitive to detect thyroglobulin antibody synthesis in mitogen-free lymphocyte cultures from 4 out of the 10 Hashimoto patients and consequently it should be possible to use this system to study the effect of various pathophysiological factors on autoantibody synthesis which would otherwise be masked by mitogenic stimulation.


Roles of neurotransmitter receptors in behavior: recovery of function following decreases in muscarinic receptor density induced by cholinesterase inhibition.
Cholinergic neurotransmitter levels were elevated in rat brain by reducing its inactivating enzyme, acetylcholinesterase (AChE), with an anti-AChE agent. Elevated levels result in decreases in cholinergic (muscarinic) receptors. Withdrawal of agent after 10 days of chronic treatment began a gradual return of neurochemical variables toward normal states, yet not fully achieving them within the following 29 days of the experiment. All behavioral and physiological variables measured showed significant effects at the start of the treatment period, developing tolerance at different rates as treatments continued. They also recovered differentially during withdrawal. Results are consistent with a theoretical model in which thresholds for normal functioning of different behavioral and physiological processes are associated with different receptor densities.


Methodological Investigation of Time Perspective Scoring and Quality of Life among Individuals with Multiple Sclerosis.
Achieving and maintaining a high quality of life following the diagnosis of chronic illness has a positive impact on the experience of illness, including delayed disease progression and fewer relapses. Time perspective has shown promising relationships with quality of life, though studies using the construct in samples with chronic illness are sparse and methodologically heterogeneous. Participants (n = 123) were diagnosed with relapsing-remitting multiple sclerosis at least five years prior to enrollment and were beginning a new disease modifying therapy (DMT). The Zimbardo Time Perspective Inventory (ZTPI) and the World Health Organization Quality of Life (WHOQoL-100) assessment were administered at baseline and the WHOQoL-100 was administered six-weeks after starting the new DMT. This study investigated the utility of three common methods of scoring and interpreting ZTPI (balanced vs. deviation-from-balanced, categorical, and continuous scores) to predict change in quality of life. Independent sample t-tests revealed no difference in quality of life for balanced vs. deviation-from-balanced. One-way ANOVA revealed no difference in quality of life across time perspective categories. Linear regression analysis found that past-negative scores predicted decreases in all quality of life domains as well as overall score while present hedonistic scores predicted increases in psychological and overall quality of life.


Communication skills competencies: definitions and a teaching toolbox.
Doctors' interpersonal and communication skills correlate with improved health care outcomes. International medical organisations require competency in communication skills. The Accreditation Council for Graduate Medical Education (ACGME) developed a toolbox for assessing this competency and 5 others, yet none initially for teaching these skills. The original focus in the development of the ACGME competencies was evaluation. This paper represents a significant step toward defining methods for teaching communication skills competencies. A total of 16 medical education leaders from medical schools worldwide, participating in the 2003 Harvard Macy Institute Program for Physician Educators, worked together to: (1) further define the ACGME competency in interpersonal and communication skills; (2) delineate teaching strategies for each level of medical education; and (3) create a teaching toolbox to integrate communication skills competencies into medical curricula. Four subgroups defined subcompetencies, identified teaching strategies for undergraduate, graduate and postgraduate medical training and brought their work to the larger group. The expanded communication competencies and teaching strategies were determined by a consensus of the larger group, presented to 80 Harvard Macy Scholars and Faculty for further discussion, then finalised by consensus. The teaching toolbox expands the ACGME core communication competencies, adds 20 subcompetencies and connects these competencies to teaching strategies at each level of medical training. It represents the collaboration and consensus of a diverse international group of medical education leaders in a variety of medical specialities and institutions, all involved in teaching communication skills. The toolbox is applicable globally across different settings and specialities, and is sensitive to different definitions of health care.


Second toe transfer for thumb reconstruction in multiple digit amputations including thumb and basal joint.
Amputation of the thumb, including the basal joint, is a disabling injury that leaves limited reconstructive options. Three cases of multiple digit amputation including the thumb and basal joint are presented in which a second toe transfer was used to reconstruct the thumb. All patients have functional pinch with an average pinch strength of 27% of the opposite uninjured extremity. The average grip strength for two patients is 44% of the opposite hand. Average motion of the transfer at the MP, PIP, and DIP is 25 degrees, 37 degrees, and 9 degrees, respectively. Adduction and abduction are obtained, the degree depending on the site of proximal bony fixation. No patient has morbidity at the donor site and all are happy with their reconstruction. In selected cases we feel second toe transfer is an excellent choice to reconstruct the thumb amputated at a proximal level.


Chlamydia pneumoniae infection is frequent but not associated with coronary arteriosclerosis in cardiac transplant recipients.
We sought to explore the relation between Chlamydia pneumoniae, cytomegalovirus (CMV), and cardiac transplant-associated arteriosclerosis. Serologic evidence of past Chlamydia pneumoniae infection was investigated in 3 patient groups at the time of cardiac catheterization: cardiac transplant recipients (n=49), patients having coronary artery bypass grafting (CABG) (n=39), and a control group free of angiographic coronary artery disease (n=21). High Chlamydia pneumoniae immunoglobulin G titers (> or =1:160) were more frequently observed in cardiac transplant recipients (odds ratio[OR] 13.7; 95% confidence intervals [CI] 1.6 to 117.4, p <0.05) and CABG patients (OR 21.7; 95% CI 1.6 to 287.0, p <0.05) than in controls. However, high Chlamydia pneumoniae titers did not distinguish between cardiac transplant recipients with or without angiographic transplant-associated arteriosclerosis or CABG patients with or without bypass vein graft disease. Furthermore, there was no significant relation between elevated Chlamydia pneumoniae titers and the presence or progression of transplant-associated arteriosclerosis in the subgroup of patients who were also CMV positive. Yet, analysis of the same angiograms demonstrated an association between CMV infection and the recent progression of transplant-associated arteriosclerosis. Thus, patients with cardiac transplantation have evidence of past Chlamydia pneumoniae and CMV infection but Chlamydia pneumoniae does not appear to have an independent role or synergistic relation to CMV in the development of transplant-associated arteriosclerosis.


Styrene copolymers as pollutant adsorbents. Safe sampling volume determination.
The determination of safe sampling volumes of benzene and acetone on air samplers filled with Porapak Q, Chromosorb 101, 102 and 103 is described. Two direct methods are employed; one method is based on frontal chromatography, while the second one is a concentration method followed by thermal desorption. The results are compared to those determined by the indirect pulse chromatographic method. The safe sampling volumes determined by the direct methods were in accordance. The indirect method gives slightly different values; however, this procedure is carried out at "infinite dilution". The effect of the pollutant concentration on the safe sampling volumes was also examined. The values decrease with increasing pollutant concentration.