Analytical Validation and Clinical Qualification of a New Immunohistochemical Assay for Androgen Receptor Splice Variant-7 Protein Expression in Metastatic Castration-resistant Prostate Cancer.
The androgen receptor splice variant-7 (AR-V7) has been implicated in the development of castration-resistant prostate cancer (CRPC) and resistance to abiraterone and enzalutamide. To develop a validated assay for detection of AR-V7 protein in tumour tissue and determine its expression and clinical significance as patients progress from hormone-sensitive prostate cancer (HSPC) to CRPC. Following monoclonal antibody generation and validation, we retrospectively identified patients who had HSPC and CRPC tissue available for AR-V7 immunohistochemical (IHC) analysis. Nuclear AR-V7 expression was determined using IHC H score (HS) data. The change in nuclear AR-V7 expression from HSPC to CRPC and the association between nuclear AR-V7 expression and overall survival (OS) was determined. Nuclear AR-V7 expression was significantly lower in HSPC (median HS 50, interquartile range [IQR] 17.5-90) compared to CRPC (HS 135, IQR 80-157.5; p<0.0001), and in biopsy tissue taken before (HS 80, IQR 30-136.3) compared to after (HS 140, IQR 105-167.5; p=0.007) abiraterone or enzalutamide treatment. Lower nuclear AR-V7 expression at CRPC biopsy was associated with longer OS (hazard ratio 1.012, 95% confidence interval 1.004-1.020; p=0.003). While this monoclonal antibody primarily binds to AR-V7 in PC biopsy tissue, it may also bind to other proteins. We provide the first evidence that nuclear AR-V7 expression increases with emerging CRPC and is prognostic for OS, unlike antibody staining for the AR N-terminal domain. These data indicate that AR-V7 is important in CRPC disease biology; agents targeting AR splice variants are needed to test this hypothesis and further improve patient outcome from CRPC. In this study we found that levels of the protein AR-V7 were higher in patients with advanced prostate cancer. A higher level of AR-V7 identifies a group of patients who respond less well to certain prostate cancer treatments and live for a shorter period of time.


Tracking the Verwey Transition in Single Magnetite Nanocrystals by Variable-Temperature Scanning Tunneling Microscopy.
Variable-temperature scanning tunneling spectroscopy revealed a sharp Verwey transition in individual ∼10 nm magnetite nanocrystals prepared by the coprecipitation technique and embedded in the surface of a gold film. The transition was observed as a significant change in the electronic structure around the Fermi level, with an apparent band gap of ∼140-250 meV appearing below the transition temperature and a pseudogap of ∼75 ± 10 meV appearing above it. The transition temperature was invariably observed around 101 ± 2 K for different nanocrystals, as opposed to 123 K typically reported for stoichiometric bulk crystals. This suggests that the lowering of the transition temperature is an intrinsic finite size effect, probably due to the presence of the surface.


Drug delivery system based on dendritic nanoparticles for enhancement of intravesical instillation.
Intravesical instillation of antitumor agents following transurethral resection of bladder tumors is the standard strategy for the treatment of superficial bladder cancers. However, the efficacy of current intravesical instillation is limited partly due to the poor permeability of the urothelium. We therefore aimed to develop a high-penetrating, target-releasing drug delivery system to improve the efficacy of intravesical instillation. PAMAM, a dendrimer, were conjugated with polyethylene glycol (PEG) to form PEG-PAMAM complex as a nanocarrier. Doxorubicin (DOX) was then encapsulated into PEG-PAMAM to generate DOX-loaded PEG-PAMAM nanoparticles (PEG-PAMAM-DOX). Our results indicated that the PEG-PAMAM was a stable nanocarrier with small size and great biosafety. The release of DOX from PEG-PAMAM-DOX was sluggish but could be effectively triggered in an acid microenvironment (pH =5.0). As a drug carrier, PEG-PAMAM could penetrate mice bladder urothelium effectively and increase the amount of DOX within the bladder wall after intravesical instillation. The antitumor effect of PEG-PAMAM-DOX was evaluated using an orthotopic bladder cancer model in mice. Compared to free DOX, PEG-PAMAM-DOX showed significantly improved efficacy of DOX for intravesical instillation with limited side effects. In conclusion, we successfully developed a PEG-PAMAM-based drug delivery system to enhance the antitumor effect of intravesical instillation.


The effect of tissue elastic properties and surfactant on alveolar stability.
This paper presents a novel mathematical model of alveoli, which simulates the effects of tissue elasticity and surfactant on the stability of human alveoli. The model incorporates a spherical approximation to the alveolar geometry, the hysteretic behavior of pulmonary surfactant and tissue elasticity. The model shows that the alveolus without surfactant and the elastic properties of the lung tissue are always at an unstable equilibrium, with the capability both to collapse irreversibly and to open with infinite volume when the alveolus has small opening radii. During normal tidal breathing, the alveolus can becomes stable, if surfactant is added. Including the passive effect of tissue elasticity stabilizes the alveolus, further allowing the alveoli to be stable, even for lung volumes below residual volume. The model is the first to describe the combined effects of tissue elasticity and surfactant on alveolar stability. The model may be used as an integrated part of a more comprehensive model of the respiratory system, since it can predict opening pressures of alveoli.


Alpha1 adrenergic receptors activate phosphatidylinositol 3-kinase in human vascular smooth muscle cells. Role in mitogenesis.
Activation of alpha1 adrenergic receptors stimulates mitogenesis in human vascular smooth muscle cells (HVSMCs). To examine signaling pathways by which activation of alpha1 receptors may induce mitogenesis in HVSMCs, we have found that alpha1 receptor stimulated-DNA synthesis and activation of mitogen-activated protein (MAP) kinase are blocked by wortmannin, an inhibitor of phosphatidylinositol 3-kinase (PI 3-kinase). To determine directly if activation of alpha1 receptors stimulated PI 3-kinase, in vitro assays of kinase activity were performed in immunocomplexes precipitated by an antibody against the p85 alpha subunit of PI 3-kinase. Noradrenaline stimulated a time- and concentration-dependent activation of PI 3-kinase in the presence of a beta adrenergic receptor antagonist. Noradrenaline-stimulated PI 3-kinase activation was blocked by antagonists of alpha1 receptors and by pertussis toxin, suggesting that alpha1 receptors activate PI 3-kinase via a pertussis toxin-sensitive G protein. Direct activation of protein kinase C by a phorbol ester did not stimulate PI 3-kinase; also, a Ca2+ L-channel blocker did not inhibit noradrenaline-stimulated PI 3-kinase activity. Increased PI 3-kinase activity was detected in both anti-Ras and anti-phosphotyrosine immunoprecipitates from noradrenaline-stimulated HVSMCs. Moreover, noradrenaline stimulated formation of active Ras-GTP complexes. Because blockade of PI 3-kinase by wortmannin inhibited formation of this complex, this result suggests that Ras might be a target of PI 3-kinase. Noradrenaline stimulated tyrosine phosphorylation of the p85 subunit of PI 3-kinase, and a phosphorylated tyrosine protein could be co-immunoprecipitated with anti-p85 of PI 3-kinase. These results demonstrate that stimulation of alpha1 receptors activates PI 3-kinase in HVSMCs and that alpha1 receptor-activated PI 3-kinase is associated with an increase in active Ras-GTP and activation of tyrosine protein phosphorylation. These pathways may contribute to alpha1 receptor-stimulated mitogenic responses including activation of MAP kinase and DNA synthesis in HVSMCs.


Hv1-deficiency protects β cells from glucotoxicity through regulation of NOX4 level.
High glucose (HG)-induced oxidative stress contributes to the dysfunction of pancreatic β cells in diabetes. The voltage-gated proton channel Hv1 has been proposed to support reactive oxygen species (ROS) production during respiratory bursts. However, the effect of Hv1 on glucotoxicity in pancreatic β cells is not clear yet. In this study, we examined the protective effects of Hv1-deficiency in HG cultured β cells. Following 48 h of treatment with 30 mM high glucose, Hv1 KO β cells showed higher cell viability, lower cell apoptosis and a more stable insulin gene expression level compared to WT β cells. In both control and HG cultured β cells, deficiency of Hv1 decreased the glucose- and PMA-induced ROS production. Finally, HG incubation led to NOX4 upregulation in WT β cells, which could be inhibited by HV1 deficiency. In conclusion, Hv1-deficiency prevents the HG treatment-induced NOX4 upregulation and protects β cells from glucotoxicity.


Behavior and gastroesophageal reflux in the premature neonate.
The belief that behavioral observations assist in the clinical diagnosis of gastroesophageal reflux (GER) disease in premature neonates has not been formally tested. The purpose of this study was to determine whether esophageal acidification was associated with a recognizable pattern of behavioral changes in these infants. The behavior of 14 healthy premature infants was recorded by a video camera while esophageal pH was simultaneously monitored. For each of 20 acid GER episodes recorded, a 10-minute video epoch, encompassing the onset of acid GER and lasting at least 4 minutes after the onset of GER, was examined. Two independent observers each scored reflux-associated epochs of "general" infant behavior and behavior previously shown to be indicative of reflux in normal term infants. The occurrence of esophageal acidification due to reflux did not significantly alter scores for general behavior. Infants frequently demonstrated reflux-specific behavior, including discomfort, head retraction, and mouthing; however, none of these behavioral patterns was temporally associated with the occurrence of acid GER. These data indicate that reflux-specific behavioral criteria, established in older term infants, may be inappropriate as diagnostic criteria for GER in premature neonates and may lead to the unnecessary use of antireflux therapy.


The costs and benefits in an unusual symbiosis: experimental evidence that bitterling fish (Rhodeus sericeus) are parasites of unionid mussels in Europe.
Interspecific symbiotic relationships involve a complex network of interactions, and understanding their outcome requires quantification of the costs and benefits to both partners. We experimentally investigated the costs and benefits in the relationship between European bitterling fish (Rhodeus sericeus) and freshwater mussels that are used by R. sericeus for oviposition. This relationship has hitherto been thought mutualistic, on the premise that R. sericeus use mussels as foster parents of their embryos while mussels use R. sericeus as hosts for their larvae. We demonstrate that R. sericeus is a parasite of European mussels, because it (i) avoids the cost of infection by mussel larvae and (ii) imposes a direct cost on mussels. Our experiments also indicate a potential coevolutionary arms race between bitterling fishes and their mussel hosts; the outcome of this relationship may differ between Asia, the centre of distribution of bitterling fishes, and Europe where they have recently invaded.


A flower-inducing substance of high molecular weight from higher plants.
The flower-inducing activities of aqueous extracts of several plants were fractionated by gel filtration. Three major peaks, corresponding to molecular weights of about 120, 20 to 30, and 5 to 10 kilodaltons, were detected in extracts of Lemna, Pharbitis, and Brassica. The latter two peaks may be degradation products generated during the extraction procedure. In extracts of soybean seeds, only the peak of material of 120 kilodaltons was detected. This is the first published report of a high molecular mass substance with florigenic activity in Lemna plants. The florigenic substance had some properties associated with proteins (or polypeptides), but the activity was unaffected by treatment with proteinase K.


Expression and activation of pro-MMP-2 and pro-MMP-9 during rat liver regeneration.
Partial hepatectomy triggers a variety of biological phenomena, which culminate in regeneration of the liver mass. Hepatocyte proliferation is a major feature of the regenerating liver after partial hepatectomy. Previous studies in our laboratory suggested that hepatic matrix remodeling might be a prerequisite process for hepatocyte proliferation in the regenerating liver. In the present study we use immunohistochemical staining, Western blot analysis, and gelatin zymography to show that the inactive matrix metalloproteinases (MMPs), pro-MMP-2 and pro-MMP-9, are elevated at 30 minutes and activated at 6 to 12 hours and at 3 to 6 hours, respectively, after hepatectomy. Sham-operated livers did not show an increase in inactive pro-MMP-2 and pro-MMP-9 and did not contain active MMP-2 or MMP-9. To examine whether tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) is changed to regulate the activities of MMPs after partial hepatectomy, the level of TIMP-1 protein was analyzed by both immunohistochemistry and Western blot analysis. The level of TIMP-1 protein appears to increase by 6 to 18 hours, implying that an increase in TIMP-1 regulates activities of active MMP-2 and MMP-9. Taken together, these results suggest that hepatic matrix remodeling is mediated by activated MMPs, which contribute to modulation of the environment surrounding hepatocytes during rat liver regeneration.


[Transcranial direct current stimulation: new clinical roadmaps for psychiatric research].
Transcranial direct current stimulation (tDCS) is a neuromodulatory technique that has undergone intensive research over the past decade with promising results. tDCS is based on the application of weak, direct current over the scalp, leading to cortical hypo- or hyperpolarization according to the specified parameters. Recent studies have shown that tDCS is able to induce potent changes in cortical excitability as well as to elicit long-lasting modifications in brain activity. Over the last decade, tDCS physiological mechanisms of action have been intensively investigated. This research has given support for the investigation of tDCS applications in a wide range of clinical populations, including patients with post-stroke motor and language deficits, chronic pain, and tinnitus. Recently, its efficacy to treat psychiatric conditions has been explored increasingly. In this review, we will gather clinical studies involving tDCS to ameliorate psychiatric symptoms and discuss reasonable next steps in this direction.


Vascular expression of angiotensin type 2 receptor in the adult rat: influence of angiotensin II infusion.
The aim of this study was to investigate the relative role of the angiotensin type 1 (AT1) and type 2 (AT2) receptors in mediating angiotensin II-induced regulation of AT2 receptor in mesenteric artery. Sprague-Dawley rats were infused with either angiotensin II or vehicle for 14 days at a dose of 58.3 ng/min. Ang II-infused rats were allocated to receive either an AT1 antagonist, valsartan at a dose of 30 mg/kg per day or the AT2 receptor antagonist PD123319 at a dose of 830 ng/min. Gene and protein expression of the AT2 receptor in the mesenteric vasculature was assessed by quantitative reverse transcriptase polymerase chain reaction, immunohistochemistry and by in vitro autoradiography with a specific radioligand, 1251-CGP 42112B. The AT2 receptor mRNA and protein were detected in the mesenteric artery from adult rats. Both nuclear emulsion and immunohistochemical staining showed expression of the AT2 receptor in the adventitial and medial layers. Compared to control rats, angiotensin II infusion was associated with a significant increase in the AT2 receptor expression. Valsartan treatment significantly reduced AT2 receptor gene expression, with no significant effect of PD123319 on this parameter. This study confirms that the presence of the AT2 receptor in mesenteric arteries in adult rats, shows an up-regulation of the AT2 receptor following angiotensin II infusion and suggests a role for the AT1 receptor in this regulation. In view of the recently demonstrated effects of the AT2 receptor, these findings may be relevant to the role of the AT2 receptor in the pathophysiology of vascular remodeling.


Dolutegravir versus placebo in subjects harbouring HIV-1 with integrase inhibitor resistance associated substitutions: 48-week results from VIKING-4, a randomized study.
The Phase III VIKING-3 study demonstrated that dolutegravir (DTG) 50 mg twice daily was efficacious in antiretroviral therapy (ART)-experienced subjects harbouring raltegravir- and/or elvitegravir-resistant HIV-1. VIKING-4 (ING116529) included a placebo-controlled 7-day monotherapy phase to demonstrate that short-term antiviral activity was attributable to DTG. VIKING-4 is a Phase III randomized, double-blind study in therapy-experienced adults with integrase inhibitor (INI)-resistant virus randomized to DTG 50 mg twice daily or placebo while continuing their failing regimen (without raltegravir or elvitegravir) for 7 days (clinicaltrials.gov identifier NCT01568892). At day 8, all subjects switched to open-label DTG 50 mg twice daily and optimized background therapy including ≥1 fully active drug. The primary end point was change from baseline in plasma HIV-1 RNA at day 8. The study population (n=30) was highly ART-experienced with advanced HIV disease. Patients had extensive baseline resistance to all approved antiretroviral classes. Adjusted mean change in HIV-1 RNA at day 8 was -1.06 log10 copies/ml for the DTG arm and 0.10 log10 copies/ml for the placebo arm (treatment difference -1.16 log10 copies/ml [-1.52, -0.80]; P<0.001). Overall, 47% and 57% of subjects had plasma HIV-1 RNA <50 and <400 copies/ml at week 24, and 40% and 53% at week 48, respectively. No discontinuations due to drug-related adverse events occurred in the study. The observed day 8 antiviral activity in this highly treatment-experienced population with INI-resistant HIV-1 was attributable to DTG. Longer-term efficacy (after considering baseline ART resistance) and safety during the open-label phase were in-line with the results of the larger VIKING-3 study.


GPC6, a novel member of the glypican gene family, encodes a product structurally related to GPC4 and is colocalized with GPC5 on human chromosome 13.
Glypicans are a family of cell surface heparan sulfate proteoglycans that appear to play an important role in cellular growth control and differentiation, as is supported by the observation that mutations in GPC3 are responsible for Simpson-Golabi-Behmel syndrome (SGBS) in humans. Recently it has been shown that the GPC4 gene is tightly clustered with GPC3 on the X chromosome and that some patients with SGBS apparently have deletions affecting both genes. We report here the identification of a human cDNA encoding a novel glypican family member, glypican-6. This cDNA encodes a predicted protein of 554 amino acids and is structurally analogous to other members of the glypican gene family, but most highly related to glypican-4. A single GPC6 mRNA of 6.2 kb is detected most abundantly in the ovary, liver, and kidney, with lower levels of mRNA expression also detected in a wide range of other adult tissues. Radiation hybrid analysis mapped the GPC6 gene to human chromosome 13 very near the GPC5 gene, a member of the glypican family bearing strong similarity to GPC3.


Trialkyltin compounds enhance human CG secretion and aromatase activity in human placental choriocarcinoma cells.
Human choriocarcinoma cell lines have been used as placental models for the study of endocrine function, including aromatase (CYP19) activity and the secretion of human CG (hCG). In the present study, we investigated the effects of trialkyltin compounds, which are suspected endocrine disrupters, on aromatase activity and hCG secretion in human choriocarcinoma JAR, JEG-3, and BeWo cells. Protein synthesis as measured by (35)S-methionine incorporation in all cell lines was markedly decreased by treatment with both tributyltin (TBT) and triphenyltin (TPT) at concentrations above 3 x 10(-7) M, due to cytotoxicity. In JAR cells, (35)S-methionine uptake was decreased by 50% at 3 x 10(-7) M of TBT. At a TPT concentration of 1 x 10(-7) M, protein synthesis in JAR cells was not affected, whereas JEG-3 and BeWo cells demonstrated slightly decreases. In all cell lines, both TBT and TPT increased levels of hCG secretion and aromatase activity in a dose- and time-dependent fashion following exposure to nontoxic concentration ranges. In addition, these trialkyltin compounds enhanced 8-bromo-cAMP-induced hCG secretion and aromatase activity in JAR cells. TBT caused dose-related increases in steady-state mRNA levels of both hCGbeta and CYP19 in JAR cells following 24- or 48-h exposure to nontoxic concentrations of TBT. However, these mRNA changes in JAR cells were not comparable to the changes in both hCG secretion and aromatase activity. These results indicate that the observed trialkyltin-induced alterations in human choriocarcinoma cells are due to other mechanism in addition to a regulation of hCG and CYP19 mRNA levels. Our studies suggest that trialkyltin compounds are potent stimulators of human placental hCG production and aromatase activity in vitro; and the placenta represents a potential target organ for trialkyltin compounds, whose endocrine-disrupting effects might be the result of local changes in hCG and estrogen concentrations in pregnant women.


Coupling of HPLC with electrospray ionization mass spectrometry for studying the aging of ultrasmall multifunctional gadolinium-based silica nanoparticles.
Sub-5 nm multimodal nanoparticles have great potential for theranostic applications due to their easy renal elimination combined with complementary imaging properties and therapeutic facilities. Their potential clinical use requires the full characterization of not only the nanoparticle but also all its possible degradation products. We have recently proposed new ultrasmall gadolinium-based nanoparticles for multimodal imaging and radiosensitization. The aim of this article is to describe an analytical tool to characterize degradation products in a highly diluted medium. We demonstrate that HPLC coupled to electrospray ionization mass spectrometry (ESI-MS) can be used in order to determine precisely the composition of nanoparticles and their degradation fragments during aging.


Obtention and engineering of non-human primate (NHP) antibodies for therapeutics.
Recombinant antibodies are therapeutic molecules of choice regarding their efficacy, pharmacokinetics and tolerance - all the more if they are human. The efficacy of antibodies generally depends on their affinity for their antigens. The most straightforward approach to isolate human antibodies with high affinities is the construction and screening of human immune libraries, but Humans cannot be immunized with all antigens of interest, for ethical and practical reasons. We circumvented that difficulty by utilizing non-human primates (NHP) instead of Humans and, in the course of our different studies, we have obtained several antibody fragments with high or very high affinities (from 3 nM to 50 pM) and neutralizing properties. The framework regions (FR) - the regions most implicated in tolerance - of these NHP antibody fragments were shown to be very similar to FR encoded by human germline genes. In one case, in a process called "germline humanization" (or "super-humanization"), we have increased that level of similarity and managed to go even beyond the level observed for human antibodies, without any loss of affinity. Here, the methodological peculiarities of our approach, in comparison with immune libraries built from immunised Humans, and the rationales behind these peculiarities, will be reviewed. The isolation of NHP antibody fragments from immune libraries, followed by the "super-humanization" process, opens a new and highly efficient approach for the production of high-quality recombinant antibodies for therapeutic uses.


Two endogenous substrates for polyphenoloxidase in pericarp tissues of postharvest rambutan fruit.
The catalytic oxidation of phenolic substrates by polyphenoloxidase (PPO) causes pericarp browning of postharvest rambutan fruit. In the present study, PPO and its endogenous substrates were extracted from rambutan pericarp tissues (RPT). The substrate extracts were sequentially partitioned with ethyl acetate and n-butanol. The analysis of total phenolic content showed that the most phenolic compounds were distributed in ethyl acetate fraction. By high-performance liquid chromatography (HPLC), (-)-epicatechin (EC) and proanthocyanidin A2 (PA2) were identified from this fraction. After reacting with rambutan PPO, EC turned brown rapidly within 10 min, indicating that it was a significant endogenous substrate. Although PA2 could also be oxidized by the PPO, it turned brown very slowly. In addition, because EC and PA2 were continually catalyzed into browning products by PPO during storage of the fruit at 4 and 25 degrees C, their contents in RPT gradually declined with the extended storage time. It was further observed that both substrate contents in rambutan fruit storing at 25 degrees C decreased more rapidly than that storing at 4 degrees C, suggesting that low temperature inhibited the catalytic oxidation of substrates so as to slow down pericarp browning. Practical Application: Pericarp browning is a serious problem to storage and transport of harvested rambutan fruit. A generally accepted opinion on the browning mechanism is the oxidation of phenolic substrates by PPO. Ascertaining PPO substrates will effectively help us to control enzymatic reaction by chemical methods so as to delay or even prevent pericarp browning of harvested rambutan fruit.


Hormonal control of somatic embryo development from cultured cells of caraway: interactions of abscisic Acid, zeatin, and gibberellic Acid.
The effects of abscisic acid, zeatin, and gibberellic acid on the development of somatic embryos from cultured cells of caraway (Carum carvi L.) were observed.Somatic embryos complete development on a basal medium without exogenous hormones, but some are subject to developmental abnormalities including malformed cotyledons and accessory embryos. Both zeatin and gibberellic acid, especially in combination, stimulate growth and increase the frequency of aberrant forms. Zeatin causes the formation of multiple shoots, leafy and abnormal cotyledons, and in the dark, enlarged hypocotyls; gibberellic acid effects root elongation, polycotyledony, and some callus formation. In contrast, abscisic acid, at concentrations which do not inhibit embryo maturation, selectively suppresses abnormal proliferations. With abscisic acid, and especially in the dark, a high percentage of embryos complete development with two fleshy cotyledons on unelongated axes free of accessory embryos.In the light, zeatin eliminates abscisic acid inhibition while gibberellic acid only partially counters its effect, promoting elongated radicles and green rather than white cotyledons. In the dark, zeatin in combination with abscisic acid stimulates extensive callusing. Gibberellic acid does not reverse the effects of abscisic acid but rather enhances them and can counter the disruptive effects of zeatin.The results demonstrate that the balance between abscisic acid on the one hand and zeatin and gibberellic acid on the other can effectively control somatic embryo development and either disrupt or ensure normal maturation.


Blood group gene frequency in a selected north Indian population.
Gene frequencies have been calculated from 6334 blood donors who were tested at a referral hospital in north India, for ABO & Rh and from > 350 donors who were tested for other blood groups. The Hardy Weinberg equation for 2 allel systems and the Bernstein method for 3 or more allel systems have been employed for calculating gene frequencies. The predominance of blood group B (37.39%), Rh D negative frequency of 4.63 per cent, predominance of M gene (0.6383) and M s haplotype (0.4464) and S gene frequency below 0.3 (0.2069) agrees with earlier data. The new findings include the presence of the allels Fy (a-b-) (0.44%) in the Duffy group, S- s- (1.16%) in the Ss group and JK (a-b-) (0.54%) in the Kidd blood group system. These have not been reported in the Indian population.


Evaluating the effects of the preoxidation of H2O2, NaClO, and KMnO4 and reflocculation on the dewaterability of sewage sludge.
The preoxidation effects of H2O2, NaClO, and KMnO4 on the dewaterability of sewage sludge were compared by analyzing the changes in specific resistance to filtration (SRF), filter cake moisture content (FCMC), extracellular polymeric substance (EPS) fractions and components, and floc properties. The three oxidants varied in oxidation efficiency and exhibited distinctive mechanisms. NaClO not only destroyed sludge flocs and EPSs but also effectively caused cell lysis, resulting in release of a considerable amount of organic matters and subsequently significant deterioration of dewatering performance. The oxidation of H2O2 and KMnO4 was relatively mild and occurred mainly on the outer layers of the sludge flocs and cell-bound EPSs. By contrast, the SRF and FCMC of the sludge conditioned with a low dose of KMnO4 were slightly improved, and a fraction of soluble EPS was compressed because of the coagulation effect of the oxidation product MnO2. The pH of the sludge conditioned with H2O2 and KMnO4 showed no considerable change. Meanwhile, NaClO evidently increased the alkalinity of the sludge because of the hydrolysis effect. After the pH of the NaClO-treated sludge was readjusted to 7.0, the partial protonation efficiency slightly alleviated the deterioration of sludge dewatering performance. The preoxidized sludge was then subjected to reflocculation treatment using FeCl3, polyacrylamide, and a cationic starch-based flocculant, respectively. The combined treatment of preoxidation and reflocculation showed a high dewatering efficiency owing to their synergistic effect.


Characterization and Quantification of Particle-Bound Criegee Intermediates in Secondary Organic Aerosol.
The ozonolysis of alkenes contributes substantially to the formation of secondary organic aerosol (SOA), which are important modulators of air quality and the Earth's climate. Criegee intermediates (CIs) are abundantly formed through this reaction. However, their contributions to aerosol particle chemistry remain highly uncertain. In this work, we present the first application of a novel methodology, using spin traps, which simultaneously quantifies CIs produced from the ozonolysis of volatile organic compounds in the gas and particle phases. Only the smallest CI with one carbon atom was detected in the gas phase of a β-caryophyllene ozonolysis reaction system. However, multiple particle-bound CIs were observed in β-caryophyllene SOA. The concentration of the most abundant CI isomer in the particle phase was estimated to constitute ∼0.013% of the SOA mass under atmospherically relevant conditions. We also demonstrate that the lifetime of CIs in highly viscous SOA particles is at least on the order of minutes, substantially greater than their gas-phase lifetime. The confirmation of substantial concentrations of large CIs with elongated lifetimes in SOA raises new questions regarding their influence on the chemical evolution of viscous SOA particles, where CIs may be a previously underestimated source of reactive species.


Synthesis of Thermogelling Poly(N-isopropylacrylamide)-graft-chondroitin Sulfate Composites with Alginate Microparticles for Tissue Engineering.
Injectable biomaterials are defined as implantable materials that can be introduced into the body as a liquid and solidify in situ. Such materials offer the clinical advantages of being implanted minimally invasively and easily forming space-filling solids in irregularly shaped defects. Injectable biomaterials have been widely investigated as scaffolds for tissue engineering. However, for the repair of certain load-bearing areas in the body, such as the intervertebral disc, scaffolds should possess adhesive properties. This will minimize the risk of dislocation during motion and ensure intimate contact with the surrounding tissue, providing adequate transmission of forces. Here, we describe the preparation and characterization of a scaffold composed of thermally sensitive poly(N-isopropylacrylamide)-graft-chondroitin sulfate (PNIPAAM-g-CS) and alginate microparticles. The PNIPAAm-g-CS copolymer forms a viscous solution in water at RT, into which alginate particles are suspended to enhance adhesion. Above the lower critical solution temperature (LCST), around 30 °C, the copolymer forms a solid gel around the microparticles. We have adapted standard biomaterials characterization procedures to take into account the reversible phase transition of PNIPAAm-g-CS. Results indicate that the incorporation of 50 or 75 mg/ml alginate particles into 5% (w/v) PNIPAAm-g-CS solutions quadruple the adhesive tensile strength of PNIPAAm-gCS alone (p<0.05). The incorporation of alginate microparticles also significantly increases swelling capacity of PNIPAAm-g-CS (p<0.05), helping to maintain a space-filling gel within tissue defects. Finally, results of the in vitro toxicology assay kit, 2,3-bis-(2-methoxy-4-nitro-5-sulfophenyl)-2H-tetrazolium-5-carboxanilide (XTT) and Live/Dead viability assay indicate that the adhesive is capable of supporting the survival and proliferation of encapsulated Human Embryonic Kidney (HEK) 293 cells over 5 days.


Natural products version 2.0: connecting genes to molecules.
Natural products have played a prominent role in the history of organic chemistry, and they continue to be important as drugs, biological probes, and targets of study for synthetic and analytical chemists. In this Perspective, we explore how connecting Nature's small molecules to the genes that encode them has sparked a renaissance in natural product research, focusing primarily on the biosynthesis of polyketides and non-ribosomal peptides. We survey monomer biogenesis, coupling chemistries from templated and non-templated pathways, and the broad set of tailoring reactions and hybrid pathways that give rise to the diverse scaffolds and functionalization patterns of natural products. We conclude by considering two questions: What would it take to find all natural product scaffolds? What kind of scientists will be studying natural products in the future?


Mitochondrial Ferritin Protects Hydrogen Peroxide-Induced Neuronal Cell Damage.
Oxidative stress and iron accumulation are tightly associated with neurodegenerative diseases. Mitochondrial ferritin (FtMt) is identified as an iron-storage protein located in the mitochondria, and its role in regulation of iron hemeostasis in neurodegenerative diseases has been reported. However, the role of FtMt in hydrogen peroxide (H2O2)-induced oxidative stress and iron accumulation in neuronal cells has not been studied. Here, we overexpressed FtMt in neuroblastoma SH-SY5Y cells and induced oxidative stress by treating with extracellular H2O2. We found that overexpression of FtMt significantly prevented cell death induced by H2O2, particularly the apoptosis-dependent cell death. The protective effects involved inhibiting the generation of cellular reactive oxygen species, sustaining mitochondrial membrane potential, maintaining the level of anti-apoptotic protein Bcl-2, and inhibiting the activation of pro-apoptotic protein caspase 3. We further explored the mechanism of these protective effects and found that FtMt expression markedly altered iron homeostasis of the H2O2 treated cells as compared to that of controls. The FtMt overexpression significantly reduced cellular labile iron pool (LIP) and protected H2O2-induced elevation on LIP. While in H2O2 treated SH-SY5Y cells, the increased iron uptake and reduced iron release, in correlation with levels of DMT1(-IRE) and ferroportin 1, resulted in heavy iron accumulation, the FtMt overexpressing cells didn't show any significant changes in levels of iron transport proteins and in the level of LIP. These results implicate a neuroprotective role of FtMt on H2O2-induced oxidative stress, which may provide insights into the treatment of iron accumulation associated neurodegenerative diseases.


Flow-mediated release of nitric oxide in isolated, perfused rabbit lungs.
The effects of changing perfusate flow on lung nitric oxide (NO) production and pulmonary arterial pressure (Ppa) were tested during normoxia and hypoxia and after N(G)-monomethyl-L-arginine (L-NMMA) treatment during normoxia in both blood- and buffer-perfused rabbit lungs. Exhaled NO (eNO) was unaltered by changing perfusate flow in blood-perfused lungs. In buffer-perfused lungs, bolus injections of ACh into the pulmonary artery evoked a transient increase in eNO from 67 +/- 3 (SE) to 83 +/- 7 parts/billion with decrease in Ppa, whereas perfusate NO metabolites (pNOx) remained unchanged. Stepwise increments in flow from 25 to 150 ml/min caused corresponding stepwise elevations in eNO production (46 +/- 2 to 73 +/- 3 nl/min) without changes in pNOx during normoxia. Despite a reduction in the baseline level of eNO, flow-dependent increases in eNO were still observed during hypoxia. L-NMMA caused declines in both eNO and pNOx with a rise in Ppa. Pulmonary vascular conductance progressively increased with increasing flow during normoxia and hypoxia. However, L-NMMA blocked the flow-dependent increase in conductance over the range of 50-150 ml/min of flow. In the more physiological conditions of blood perfusion, eNO does not reflect endothelial NO production. However, from the buffer perfusion study, we suggest that endothelial NO production secondary to increasing flow, may contribute to capillary recruitment and/or shear stress-induced vasodilation.


The value of sepsis biomarkers and their kinetics in the prognosis of septic shock due to bacterial infections.
In this study, we aim to explore the value of procalcitonin (PCT), C-reactive protein (CRP), and serum cholinesterase (SChE) activity kinetics as useful predictors of mortality in patients with septic shock admitted to the intensive care unit (ICU). We conducted a prospective single-blinded study in the ICU of a university hospital during a period of 1 year. Were included all patients 18 years of age or older, with confirmed septic shock. For all included patients, blood samples of septic biomarkers (PCT, SChE activity, and CRP) were obtained. Serum was collected at the day of ICU admission (day 0), the day of septic shock (day 1), then 3 and 5 days after the septic shock development. During the study period, 60 patients were included. The mean age (± SD) was 47.7 ± 19 years. There were 46 male (74%) and 14 female (26%) patients. Mean SAPSII on ICU admission was 40.7 ± 16 (median: 37), and mean SOFA score on ICU admission was 16 ± 4 (median: 7). During their ICU stay, out of the 60 included patients, 37 patients died (61%). The comparison between the 2 groups (deaths and survivors) showed that the factors associated with poor outcome were age, SOFA score on ICU admission, and the need for invasive mechanical ventilation. The day of septic shock, there was no difference in the mean concentrations in those of plasma SChE activity or in the PCT and CRP plasma between survivors and non-survivors. However, the comparison of mean plasma SChE activity, and PCT and CRP plasma concentrations (on day 3 and day 5) between survivors and non-survivors, showed a significant difference between the 2 groups. Our study suggests that, in a group of critically ill patients with severe septic shock, a rise or no change in procalcitonin and/or CRP level, and/or a decrease or no change in SChE activity should warn the clinician about the insufficiency and/or inadequacy of the therapy. However, a fall in procalcitonin and/or CRP levels, and/or a rise in SChE activity were associated with a favourable prognosis. Based on our study and some other data detailed above, we recommend that an estimation of SChE acti-vity, procalcitonin, and CRP on the day of septic shock, followed by estimation within the next 72-120 h, could help the prognostic assessment of critically ill patients with septic shock. Further studies are needed to define the critical values related to mortality.


Solar-light photoamperometric and photocatalytic properties of quasi-transparent TiO2 nanoporous thin films.
Transparent photocatalytic surfaces are of ever increasing importance for many applications on self-cleaning windows and tiles in everyday applications. Here, we report the formation and photocatalytic testing of a quasi-transparent thin and nanoporous titania films deposited on glass plates. Sputtered Ti thin films were anodized in fluoride-ion-containing neutral electrolytes to form optically semitransparent nanoporous films, which transformed to be completely transparent after thermal annealing. The nanoporous films were studied at different stages, such as before and after anodization, as well as after thermal annealing using scanning electron microscopy (SEM), X-ray diffraction (XRD), and UV-vis and Raman spectroscopy. It was observed that anodization at 20 V of high-temperature deposited titanium films resulted in regular nanopore films with pore diameters of 30 nm. Structural investigations on the transparent nanopore arrays reveal the presence of anatase phase TiO(2) even after annealing at 500 °C, which was confirmed by XRD and Raman spectroscopy measurements. The solar-light induced photocatalytic decomposition of stearic acid and photoconductivity characteristics of these nanoporous thin films are also presented.


Remifentanil versus alfentanil: comparative pharmacokinetics and pharmacodynamics in healthy adult male volunteers.
Remifentanil is an esterase-metabolized opioid with a rapid clearance. The aim of this study was to contrast the pharmacokinetics and pharmacodynamics of remifentanil and alfentanil in healthy, adult male volunteers. Ten volunteers received infusions of remifentanil and alfentanil on separate study sessions using a randomized, open-label crossover design. Arterial blood samples were analyzed to determine drug blood concentrations. The electroencephalogram was employed as the measure of drug effect. The pharmacokinetics were characterized using a moment analysis, a nonlinear mixed effects model (NONMEM) population analysis, and context-sensitive half-time computer simulations. After processing the raw electroencephalogram to obtain the spectral edge parameter, the pharmacodynamics were characterized using an effect compartment, inhibitory maximum effect model. Pharmacokinetically, the two drugs are similar in terms of steady-state distribution volume (VD(SS)), but remifentanil's central clearance (CLc)) is substantially greater. The NONMEM analysis population pharmacokinetic parameters for remifentanil include a CLc of 2.9 l x min(-1), a VDss of 21.81, and a terminal half-life of 35.1 min. Corresponding NONMEM parameters for alfentanil are 0.36 l x min(-1), 34.11, and 94.5 min. Pharmacodynamically, the drugs are similar in terms of the time required for equilibration between blood and the effect-site concentrations, as evidenced by a T(12)k(e0) for remifentanil of 0.75 min [corrected] and 0.96 min for alfentanil. However, remifentanil is 19 times more potent than alfentanil, with an effective concentration for 50% maximal effect of 19.9 ng x ml(-1) versus 375.9 ng x ml(-1) for alfentanil. Compared to alfentanil, the high clearance of remifentanil, combined with its small steady-state distribution volume, results in a rapid decline in blood concentration after termination of an infusion. With the exception of remifentanil's nearly 20-times greater potency (30-times if alfentanil partitioning between whole blood and plasma is considered), the drugs are pharmacodynamically similar.


Drug-Target Interactions: Prediction Methods and Applications.
Identifying the interactions between drugs and target proteins is a key step in drug discovery. This not only aids to understand the disease mechanism, but also helps to identify unexpected therapeutic activity or adverse side effects of drugs. Hence, drug-target interaction prediction becomes an essential tool in the field of drug repurposing. The availability of heterogeneous biological data on known drug-target interactions enabled many researchers to develop various computational methods to decipher unknown drug-target interactions. This review provides an overview on these computational methods for predicting drug-target interactions along with available webservers and databases for drug-target interactions. Further, the applicability of drug-target interactions in various diseases for identifying lead compounds has been outlined.


Pharmacokinetics of oral cyclosporine (Neoral) in heart transplant recipients during the immediate period after surgery.
Neoral cyclosporine has better absorption characteristics than the original Sandimmun formulation. This has allowed Neoral to be administered orally in circumstances where Sandimmun had been ineffective, including the postoperative phase of liver transplantation. Sampling strategies, such as the measurement of drug concentration 2 h after oral administration, have been used in a variety of settings to estimate systemic exposure to Neoral (measured as the area under the blood concentration curve (AUC) of the drug) in blood. We conducted a pilot study to determine whether Neoral could be administered orally immediately after heart transplantation and to determine which pharmacokinetic parameters reflect systemic drug exposure in this setting. Eight male patients (mean age 50 years) undergoing a first heart transplant were studied. Neoral was administered orally before surgery and at 12-h intervals via a nasogastric tube after surgery. Twelve-hour pharmacokinetic profiles were obtained on postoperative days 1, 3 and 5. Cyclosporine concentrations were measured with the Dade Behring Emit assay, which is specific for the parent drug. Drug concentrations were dose-normalised and drug exposure was measured by the AUC. Drug exposure following administration (AUC(0-12)) was low on day 1 but increased by 99% between postoperative day 1 and day 5 ( P<0.05), indicating more complete absorption of cyclosporine; exposure in the first 4 h post-dose (AUC(0-4)) increased by 126% ( P<0.01), reflecting more rapid cyclosporine absorption, and the maximum blood concentration observed increased by 137% ( P<0.05) during the same period. The correlation between the cyclosporine trough concentration and AUC(0-12) was low on all days. Due to the changing pattern of cyclosporine absorption, concentration measurements at a single time point could not accurately predict 12-h exposure to the drug on all study days. However, the drug concentration at 2 h post-dose had a high correlation with drug exposure during the first 4 h (correlation of C(2) to AUC(0-4): r(2)>0.93 on all days). Absorption of Neoral was low immediately after heart transplantation but improved substantially during the first 5 days after surgery. No single timed measurement of drug concentration reflected cyclosporine exposure; however, the 2-h concentration did provide an accurate measure of the early phase of drug absorption (AUC(0-4)). Oral administration of Neoral may result in inadequate immunosuppression immediately after heart transplantation unless it is supplemented either by intravenous cyclosporine or by the use of an induction agent.


Exome-based mutation screening in South African children with primary congenital glaucoma.
To identify pathogenic variants in a cohort of 23 black South African children with sporadic primary congenital glaucoma (PCG) using an exome-based approach. Children with PCG were recruited from two Paediatric Ophthalmology Clinics in Johannesburg, South Africa. Whole exome sequencing was performed on genomic DNA. Of the 23 children, 19 were male and 19 had bilateral PCG. A variant prioritization strategy was employed whereby variants in known PCG genes (CYP1B1, LTBP2 and TEK) were evaluated first, followed by the identification of putative disease-causing variants in other genes related to eye diseases and phenotypes. Validated pathogenic variants in the CYP1B1 gene (c.1169 G>A; p.Arg390His) and TEK gene (c.922 G>A; p.Gly308Arg) were identified in one child each. No LTBP2 mutations were identified in this cohort. In silico predictions identified potentially damaging rare variants in genes previously associated with eye development phenotypes or glaucoma in a further 12 children. This study demonstrates the value of whole exome sequencing in identifying disease-causing variants in African children with PCG. It is the first report of a TEK disease-causing variant in an African PCG patient. Potential causative variants detected in PCG candidate genes warrant further investigation.


Changing the surface of a virus shell fusion of an enzyme to polyoma VP1.
Recent developments on virus-like particles have demonstrated their potential in transfecting eucaryotic cells. In the case of particles based on the major coat protein VP1 of polyoma virus, transfection occurs via binding of VP1 to sialic acids. Since sialic acid is present on almost every eucaryotic cell line, this results in an unspecific cell targeting. Generation of a cell-type specificity of this system would imply the presentation of a new function on the surface of VP1. To analyze whether a new functional protein can be placed on VP1, we inserted dihydrofolate reductase from Escherichia coli as a model protein. The effect of such an insertion on both VP1 and the inserted protein was investigated, respectively. The function of VP1, like the formation of pentameric capsomers and its ability to assemble into capsids, was not influenced by the insertion. The inserted dihydrofolate reductase showed major changes when compared to the wild-type form. The thermal stability of the enzyme was dramatically reduced in the fusion protein; nevertheless, the dihydrofolate reductase proved to be a fully active enzyme with only slightly increased K(M) values for its substrates. This model system provides the basis for further modifications of the VP1 protein to achieve an altered surface of VP1 with new properties.


Design, Synthesis, and Evaluation of Near-Infrared Fluorescent Molecules Based on 4H-1-Benzopyran Core.
A series of novel fluorescent 4H-1-benzopyrans was designed and developed as near-infrared fluorescent molecules with a compact donor-acceptor-donor architecture. Spectral intensity of the fluorescent molecules M-1, M-2, M-3 varied significantly with the increasing polarities of solvents, where M-3 showed high viscosity sensitivity in glycerol-ethanol system with a 3-fold increase in emission intensity. Increasing concentrations of compound M-3 to 5% BSA in PBS elicited a 4-fold increase in fluorescence intensity, exhibiting a superior environmental sensitivity. Furthermore, the in vitro cellular uptake behavior and CLSM assay of cancer cell lines demonstrated that M-3 could easily enter the cell nucleus and bind to proteins with low toxicity. Therefore, the synthesized near-infrared fluorescent molecules could provide a new direction for the development of optical imaging probes and potential further drugs.


Pulmonary vein ostium shape and orientation as possible predictors of occlusion in patients with drug-refractory paroxysmal atrial fibrillation undergoing cryoballoon ablation.
No specific data are available on the influence of pulmonary vein (PV) anatomy and shape on cryoballoon ablation (CA) catheter efficacy in delivering cryothermal energy and, consequently, in obtaining PV isolation. Among a larger series of patients (68) with drug-refractory paroxysmal atrial fibrillation who underwent CA in our department, 52 patients were included in our study. All of them had a multislice cardiac computed tomography (MSCT) before the procedure. We retrospectively evaluated their MSCT scans focusing our attention on PV ovality and orientation in the frontal plane. A fair inverse association was documented between the ovality index of the left PVs and the degree of occlusion (r=-0.486 and P<0.003 for the LSPV and r=-0.360 and P=0.033 for the LIPV), whereas no association was found between the ovality index of the right PVs and the degree of occlusion (r=-0.283 and P=0.083 for the RSPV and r=0.235 and P=0.093 for RIPV). Nevertheless, a strong inverse association was found between the orientation of the PV ostia and the degree of occlusion in each vein (r=-0.804 and P<0.001 for the LSPV, r=-0.415 and P=0.013 for LIPV, r=-0.798 and P<0.001 for the RSPV, and r=-0.867 and P<0.001 for RIPV). Pulmonary vein ostium shape and orientation evaluated by MSCT proved to be useful in predicting the degree of occlusion obtained during CA.


Analysis of the predator community of a subterranean herbivorous insect based on polymerase chain reaction.
The identity and impact of trophic linkages within subterranean arthropod communities are challenging to establish, a fact that hinders the development of conservation biological control programs of subterranean herbivores. Diabrotica virgifera (the western corn rootworm) is a severe agricultural pest that lives subterraneously during its pre-imaginal stages and succumbs to high levels of pre-imaginal mortality from unknown agents. The guts of 1500 field-collected arthropod predators were analyzed for D. virgifera-specific DNA sequences using quantitative polymerase chain reaction (qPCR). These gut analyses were used to generate relative and taxon-specific prey consumption indices for the major predator taxa and to determine relative consumption levels during D. virgifera egg and larval stages by predator feeding guilds. Laboratory feeding assays were used to determine the meal size consumed during 5 min and digestion rates of D. virgifera DNA of four predators abundant in D. virgifera-infested cornfields. More than 17 taxa consumed D. virgifera in the field. Harvestmen and small rove beetles were the most abundant predators captured, and the most frequent predators within the community to consume D. virgifera. The largest proportions of individual species' populations testing positive for D. virgifera DNA were found in ground beetles (Scarites quadriceps and Poecilus chalcites) and spiders, wolf spiders, and predaceous mites. Because of the longer duration of the egg stage, significantly more predators consumed D. virgifera eggs than larvae, but a similar proportion of the predator community fed on eggs and larvae. Predators with sucking mouthparts had a higher consumption index than chewing predators. Laboratory assays confirmed that sucking predators consume more D. virgifera DNA during 5 min than the chewing predators, and all four predators digested this DNA at a similar rate. This research substantiates that a diverse community of soil-dwelling and subterranean predators contribute to the high level of mortality incurred by D. virgifera in cornfields (approximately 99% pre-adult mortality). Moreover, qPCR is a useful tool for describing trophic relationships within subterranean food webs, a crucial step in determining the relative contributions of a diverse predator community to the population dynamics of an herbivorous arthropod.


Methadone Anonymous: A 12-Step Program for Methadone Maintained Heroin Addicts.
Methadone Anonymous (MA) is a new 12-step fellowship developed for methadone maintained heroin addicts. A total of 53 MA members completed a survey assessing factors related to methadone maintenance treatment program (MMTP) entry, drug use, MA participation, beliefs concerning effectiveness of MMTP and MA, and level of social cohesiveness. Length of time in MA was associated with a decreased use of alcohol, cocaine, and marijuana. Clients rated components of MA to be significantly more helpful to recovery than MMTP treatment components. Affiliation to five MA members known best by the respondents was significantly greater than affiliation to non-MA members. Length of time in MA was positively associated with MA affiliation. Social affiliation and endorsement of 12-step principles were positively correlated. These findings suggest that MA participation has benefits not available in professionally driven MMTP, and should be further studied.


Single Entry Posterior Parasagittal Approach Radiofrequency Neurotomy of Cervical Medial Branch: A Feasible Alternative to Conventional Approaches in the Treatment of Cervical Facet Pain.
Cervical facet joint pain is an important cause of chronic neck pain. The recommended treatment for this condition is radiofrequency (RF) neurotomy of the medial branch of dorsal rami. There have been attempts to find safe and effective ways to perform this procedure. The objective of this study is to describe the single entry posterior parasagittal approach and to evaluate the efficacy and safety of this approach compared to the conventional posterolateral approach of RF neurotomy of cervical medial branch. The record of all patients with cervical facet pain who were treated with RF neurotomy medial branch of dorsal rami between January 2016 and December 2019 were reviewed retrospectively. Comparisons were made between patients who underwent RF neurotomy with multiple skin entry posterolateral approach and those who underwent RF neurotomy with single entry posterior parasagittal approach. The primary outcome was measured as the mean changes in numerical rating scale (NRS), and the secondary outcomes were duration and complications related to both approaches. Thirty-one patients who underwent RF neurotomy via posterolateral approach were compared with 40 patients who underwent the procedure via posterior parasagittal approach. Both approaches showed a significant decrease in the NRS from baseline values. However, the differences in the NRS lowering effect at 3 and 12 months between these 2 approaches were not statistically significant. The duration of the procedure was significantly shorter with posterior parasagittal approach (44.13 ± 4.72 minutes vs 54.68 ± 7.39 minutes; P < 0.001). There were no serious complications encountered in both approaches. With comparable efficacy and safety profile between the posterior parasagittal and the conventional posterolateral approaches, the former single skin entry approach offers the added advantage of being less time-consuming. Further randomized prospective studies are necessary to validate these findings.


Identification of QTL for Grain Size and Shape on the D Genome of Natural and Synthetic Allohexaploid Wheats with Near-Identical AABB Genomes.
Grain size and shape associated with yield and milling quality are important traits in wheat domestication and breeding. To reveal the genetic factors on the D genome that control grain size and shape variation, we conducted analysis of quantitative trait loci (QTL) using the F2 and F2:3 populations derived from a common allohexaploid wheat line TAA10 and a synthetic allohexaploid wheat XX329, which have near-identical AABB genomes and different DD genomes. Based on genotyping using wheat 660K single nucleotide polymorphism (SNP) array, TAA10 and XX329 exhibited 96.55, 98.10, and 66.26% genetic similarities of A, B, and D genomes, respectively. Phenotypic evaluation revealed that XX329 had higher thousand grain weight (TGW), grain length, width, area and perimeter than TAA10 across all environments, and the grain yield per plot of XX329 increased by 17.43-30.36% compared with that of TAA10 in two environments. A total of nine environmentally stable QTL associated with grain size and shape were mapped on chromosomes 2D and 7D and verified using near isogenic lines (NILs), with the synthetic allohexaploid wheat XX329 contributing favorable alleles. Notably, a novel QTL QTgw.cau-2D controlling grain weight was first identified from the synthetic allohexaploid wheat, which may be a more desirable target for genetic improvement in wheat breeding. Collectively, these results provide further insights into the genetic factors that shaped the grain morphology during wheat evolution and domestication.


The practicality of using ozone with fruit and vegetables.
The fresh produce industry is constantly growing as a result of increasing consumer demand. Food quality and safety management are still major issues for the supply chain. The use of ozone has been identified as a feasible solution to reduce microorganisms present in food, in this way extending the shelf-life of fresh produce. A number of factors that may affect the efficiency of ozone treatment have been identified, e.g. microbial populations, ozone concentration and time of exposure, type of produce, temperature, relative humidity and packaging material, and they are briefly discussed. Furthermore, practical information derived from studies with ozone conducted by the authors and from their knowledge of the subject directs the reader's attention to the key aspects of ozone use under commercial conditions, i.e. from the practical point of view. Finally, one possible direction for future research with the postharvest use of ozone, i.e. the important role of fruit cuticle in response to this postharvest treatment, is indicated. © 2016 Society of Chemical Industry.


Radiotherapy in the treatment of primary osteosarcoma--a single center experience.
To analyze our experiences concerning radiation treatment in patients with osteosarcoma. Since 1981, 40 patients with osteosarcoma have undergone radiotherapy in Heidelberg; 3 of them were immediately lost to follow-up. Twenty patients with metastases were treated palliatively and 17 patients were treated with a curative intent. Interestingly, 14 of the 17 patients treated with a curative intent were referred to our clinic during the last 8 years, whereas the number of patients referred for palliation decreased. The mean dose applied for palliation was 47 Gy (range, 26 Gy to > 70 GyE), for cure was 59 Gy (range, 45 Gy to > 70 GyE). Local control until death could be achieved in 15 of the 20 palliatively treated patients, with a mean survival of 7 months after radiation. Five patients experienced local failure with symptom recurrence, and 3 of them had received doses > 60 Gy. At last follow-up, 3 of the 17 curatively treated patients had experienced local recurrence. Median follow-up was 32 months (range, 3-144). Estimated 5-year overall survival and local control rates were 38% and 68%, respectively. Local disease-free survival was shorter in patients treated for recurrent, inoperable or incompletely resected tumors and doses below 60 Gy. With adequate doses, long-term local control is possible even in inoperable or incompletely resected tumors. Improvements of systemic therapy and modern radiation techniques have begun to bring the possibly curative role of radiation treatment back to the fore. However, in disseminated tumors, even doses beyond 60 Gy do not guarantee local control, suggesting an extremely low radiosensitivity of certain kinds of osteosarcoma.


[Comparison of algorithms for prediction of related proteins using the method of phylogenetic profiles].
Computational interactomics deals with prediction of functionally related proteins. One approach for solving this problem using comparative genomics consists in analysis of similarities between phylogenetic profiles of proteins. In contrast to most methods, which predict only pairwise interactions between proteins, in the present work we have applied cluster analysis techniques in order to find modules of functionally related proteins. We have performed cluster analysis of phylogenetic profiles of E. coli proteins using several clustering techniques and distances between profiles. We report here, that the best correspondence in the composition of resultant clusters to known metabolic pathways is achieved using Ward's clustering together with Hamming's distance. The proposed technique of assessing predictions of the modules of functionally related proteins can be used for comparative analysis of different algorithms for computational interactomics.


Low Molecular Weight Hyaluronic Acid (500-730 Kda) Injections in Tendinopathies-A Narrative Review.
Tendinopathies are common causes of pain and disability in general population and athletes. Conservative treatment is largely preferred, and eccentric exercise or other modalities of therapeutic exercises are recommended. However, this approach requests several weeks of consecutive treatment and could be discouraging. In the last years, injections of different formulations were evaluated to accelerate functional recovery in combination with usual therapy. Hyaluronic acid (HA) preparations were proposed, in particular LMW-HA (500-730 kDa) for its unique molecular characteristics in favored extracellular matrix homeostasis and tenocyte viability. The purpose of our review is to evaluate the state-of-the-art about the role of 500-730 kDa in tendinopathies considering both preclinical and clinical findings and encourage further research on this emerging topic.


Respiratory exercise program for elderly individuals with asthma.
Asthma in older adults is frequently underdiagnosed, as reflected by approximately 60% of asthma deaths occurring in people older than age 65. The present study evaluates the effects of a respiratory exercise program tailored for elderly individuals with asthma. We are not aware of any other reports examining breathing exercises in this population. Fourteen patients concluded the 16-week respiratory exercise program. All the patients were evaluated with regard to lung function, respiratory muscle strength, aerobic capacity, quality of life and clinical presentation. After 16 weeks of this open-trial intervention, significant increases in maximum inspiratory pressure and maximum expiratory pressure (27.6% and 20.54%, respectively) were demonstrated. Considerable improvement in quality of life was also observed. The clinical evaluations and daily recorded-symptoms diary also indicated significant improvements and fewer respiratory symptoms. A month after the exercises were discontinued, however, detraining was observed. In conclusion, a respiratory exercise program increased muscle strength and was associated with a positive effect on patient health and quality of life. Therefore, a respiratory training program could be included in the therapeutic approach in older adults with asthma.


Presence of residual material following mini-hemilaminectomy in dogs with thoracolumbar intervertebral disc extrusion.
Presence of residual material following mini-hemilaminectomy in dogs (n = 9) with spontaneous thoracolumbar intervertebral disc extrusion was prospectively investigated. Volume of extruded disc material within the vertebral canal and the proportion of residual material were determined using pre- and post-operative magnetic resonance imaging. The degree of spinal cord compression, proportion of extradural material considered hemorrhage, and invasion of the articular facets were also determined. Residual material was identified in 44% of the mini-hemilaminectomies. The median percentage of residual material calculated was 7.7% of the preoperative volume. No observed effect of surgical side or site, proportion of extradural material considered hemorrhage, patient weight, and duration of clinical signs was detected.


Hyperkalaemia after radiofrequency ablation of hepatocellular carcinoma.
Radiofrequency ablation of liver tumours is a useful therapy for otherwise unresectable tumours. The complication rate is said to be low. In this case report we describe hyperkalaemia after radiofrequency ablation of a hepatocellular carcinoma in a patient with end-stage renal insufficiency.


The Interchondral Joints of Thorax in Microtia Surgery: Classification and Fabrication Strategies.
The interchondral joint between the sixth and seventh costal cartilages, called synchondrosis, assists in harvesting and fabricating the microtia framework. However, its looseness often complicates the microtia surgery. We aimed to classify the interchondral joints based on looseness and identify predictors for each subtype. Electronic chart and intraoperative photographs were reviewed for consecutive microtia patients who underwent costal cartilage graft for ear reconstruction from June 2001 to February 2020. The sixth and seventh costal interchondral joint was classified in the ascending order of looseness-direct cartilaginous fusion (class I), synovial joint (class II), and loose tissue (class III)-with a minor modification from the cadaveric study of Dr. Briscoe in 1925. χ2 Tests compared the incidence of each subtype in terms of patient variables including age, sex, chest laterality, and radiologic chest deformity. Multivariate logistic regression was used for identifying independent predictors for each subtype. Seven hundred thirty-three graft specimens were enrolled (mean age 12.1 years). Class I joint was seen in 137 (18.7%) grafts, class II in 544 (74.2%), and class III in 52 (7.1%). Female predilection was found for cartilaginous fusion (class I) (adjusted odds ratio, 1.691; P = 0.007). The incidence of loose joint (class III) was comparable, ranging from 4.6% to 12.5%, in terms of all the patient variables. Loose interchondral joints were not uncommon in microtia surgery. Patient variables were less likely to predict this anatomical variation, necessitating some knowledge of managing the framework instability. Female patients were more likely to enable easy fabrication with directly fused costal cartilages.


MAF bZIP Transcription Factor B (MAFB) Protected Against Ovalbumin-Induced Allergic Rhinitis via the Alleviation of Inflammation by Restoring the T Helper (Th) 1/Th2/Th17 Imbalance and Epithelial Barrier Dysfunction.
This work aimed to investigate the effects of MAF bZIP transcription factor B (MAFB) on the progression of allergic rhinitis (AR). Nasal mucosa was isolated from AR patients and healthy individuals from Shengjing Hospital of China Medical University. The experimental procedures were approved by the Medical Ethics Committee of Shengjing Hospital of China Medical University (2019PS341K) in accordance with the Declaration of Helsinki. Informed consents were signed by participants or a parent/legal guardian of the participants under 18 years old of age. Then, an AR mouse model with MAFB overexpression was established with 25 μg ovalbumin (OVA) sensitization on day 0, 7, 14, followed by an injection with 1×107 TU/mL lentivirus MAFB on day 19 and a nasal challenge with 500 μg OVA from day 21 to 27. The results revealed that MAFB was down-regulated in the nasal mucosa of AR patients. The up-regulation of MAFB protected the AR mice against the OVA-induced allergic symptoms (sneezing and nasal rubbing) by alleviating the OVA-induced epithelial thicknesses, goblet cell hyperplasia, and inflammation including the eosinophil and mast cell infiltration. Moreover, MAFB facilitated the T helper (Th) 1 response and inhibited the Th2 and Th17 responses by the down-regulation of T-box transcription factor 21 and the up-regulation of GATA binding protein-3 as well as retinoid-related orphan receptor-γt in the splenocytes of AR mice. MAFB was found to repress the differentiation of naive CD4+ T cells into Th2 cells. Subsequently, MAFB overexpression reversed the OVA-induced enhancement of epithelial permeability, downregulation of tight junctions, and upregulation of cadherin-26, indicating the protective role of MAFB on epithelial barrier integrity. MAFB protected against OVA-induced AR via the alleviation of inflammation by restoring the Th1/Th2/Th17 imbalance and epithelial barrier dysfunction.


Control of Fullerene Crystallization from 2D to 3D through Combined Solvent and Template Effects.
Achieving precise control of molecular self-assembly to form designed three-dimensional (3D) structures is a major goal in nanoscale science and technology. Using scanning tunnelling microscopy and density functional theory calculations, we show that a 2D covalent organic framework (COF-1) can template solution-processed C60 guest molecules to form several solvent-dependent structural arrangements and morphologies via a 2D to 3D growth process. When 1,2,4-tricholorobenzene is used as solvent, C60 molecules form a template-defined close-packed structure. When heptanoic acid is used as solvent, a range of lower density architectures that deviate from the template-defined close packing are observed. We attribute this difference to the co-adsorption of the heptanoic acid solvent molecules, which is only achieved in the presence of the template. This work demonstrates the possibility to precisely control 3D molecular self-assembly through the synergistic combination of template and solvent effects.


Developmental-Behavioral Pediatrics 13 Years After the First Board Certification: Evolving Subspecialty.
To examine and define the evolving subspecialty of developmental-behavioral pediatrics (DBP) by analyzing workforce surveys presubspecialty and postsubspecialty certification. In 2015, an electronic workforce survey was sent to the members of the American Academy of Pediatrics Section on DBP and Council on Children with Disabilities and the Society for DBP. Answers from the 1998 survey for respondents with subspecialty fellowship training were compared. Compared with the 1998 group of 265 DBPs, the 368 DBPs in the 2015 group were older, more female, and more diverse. In both groups, ≥80% evaluated and treated autism spectrum disorder (ASD), attention-deficit/hyperactivity disorder (ADHD), and developmental delays, but significantly (p < 0.001) fewer cared for children with physical disabilities (e.g., cerebral palsy [58% to 41%], multihandicapped [53% to 39%], neonatal follow-up [47% to 31%], and spina bifida [26% to 13%]) and other disorders (e.g., failure to thrive and obesity/eating disorders [27% to 15%]). Time for new patient and return visits remained the same (1.5 hours and 0.7 hours). Pediatric generalists and family practice physicians initiated most referrals; fewer 2015 DBPs (p < 0.001) reported school districts (83% to 70%) and more reported pediatric subspecialty (57% to 77%; p < 0.001) referrals. Acknowledgment of the need for more community DBP specialists increased from 66% to 80% (p < 0.001). Survey data indicated that the workforce is aging and changing. ADHD, ASD, and developmental delays are solidifying as the defining clinical focus of DBP. Current trends can identify training needs, facilitate recruitment, and advocate for system change to support the DBP workforce to respond to the great need.


Dry matter intake, body condition score, and grazing behavior of nonlactating, pregnant dairy cows fed kale or grass once versus twice daily during winter.
The objective of this study was to examine the effect of wintering pregnant, nonlactating dairy cows outdoors on either kale or grass, fed in 1 [11 kg dry matter (DM) of kale or grass + 3 kg DM of baled barley straw offered in the morning] or 2 allocations (5.5 kg DM of kale or grass grazed + 1.5 kg DM of barley straw offered morning and afternoon) per day. The body condition score (BCS) gain over the 47-d winter feeding period was higher for grass-fed (0.5 BCS units) than kale-fed cows (0.3 BCS units), but was unaffected by feeding frequency. Forage DM utilization was higher for kale-fed (97%) than grass-fed cows (76%), leading to higher estimated dry matter intake (DMI) in kale-fed (10.7 kg of DM/cow per day) than grass-fed cows (7.7 kg of DM/cow per day). Forage DM utilization and estimated DMI were not affected by feeding frequency. Prehension bite rate was greater for grass-fed (37.3 bites/min) than kale-fed cows (7.6 bites/min), but more mastication bites were required for kale-fed cows. Cumulative DMI after 2, 3, and 6 h was greater in cows allocated forage once than twice a day and for kale than grass after 3 and 6 h. Mean eating time was greater for cows offered forage once (477 min) than twice (414 min) per day. In conclusion, increasing feeding frequency from once to twice per day decreased the intake rate within the first 6 h after allocation, but did not affect total daily DMI, DM utilization or BCS gain. Thus, moving cows more frequently would not have any significant advantage. It may increase labor requirements, thereby creating a more challenging wintering management than feeding once per day.


Novel naphthalenedisulfonic acid anti-HIV-1 agents. Synthesis and activity against reverse transcriptase, virus replication and syncytia formation.
Several naphthalenedisulfonic acid derivatives have been synthesized and evaluated in four anti-HIV-1 screens. Antiviral activity was evaluated in the assays that measure inhibition of HIV-1 reverse transcriptase (RT), HIV-1 induced giant cell (syncytia) formation, and HIV-1 induced cytopathogenicity in both a laboratory and clinical strain of HIV-1. 4-acetylamino-5-hydroxy-2,7- naphthalenedisulfonic and a bis naphthalenedisulfonic acid derivative emerged as the most active compounds exhibiting activity in all assays at concentrations non-toxic to the host cells. The bis 3-amino-1,5-naphthalenedisulfonic acid derivative was the most active compound, but less active than the bis 4-amino-5-hydroxynaphthalenedisulfonic acid analog in the assays that measure RT and syncytia inhibition. However, in the assay that measured inhibition of cytopathogenicity in a clinical HIV-1 isolate, 4-acetylamino-5-hydroxy-2,7-naphthalenedisulfonic acid was the most potent analog, demonstrating an in vitro therapeutic index greater than 54. This study shows that for certain naphthalenedisulfonic acid moieties a bis derivative is not a requirement for significant anti-HIV-1 activity. These agents represent a new class of lead non-nucleoside anti-HIV-1 compounds worthy of further development for potential anti-AIDS therapy.


Traumatic-event headaches.
Chronic headaches from head trauma and whiplash injury are well-known and common, but chronic headaches from other sorts of physical traumas are not recognized. Specific information was obtained from the medical records of 15 consecutive patients with chronic headaches related to physically injurious traumatic events that did not include either head trauma or whiplash injury. The events and the physical injuries produced by them were noted. The headaches' development, characteristics, duration, frequency, and accompaniments were recorded, as were the patients' use of pain-alleviative drugs. From this latter information, the headaches were classified by the diagnostic criteria of the International Headache Society as though they were naturally-occurring headaches. The presence of other post-traumatic symptoms and litigation were also recorded. The intervals between the events and the onset of the headaches resembled those between head traumas or whiplash injuries and their subsequent headaches. The headaches themselves were, as a group, similar to those after head trauma and whiplash injury. Thirteen of the patients had chronic tension-type headache, two had migraine. The sustained bodily injuries were trivial or unidentifiable in nine patients. Fabrication of symptoms for financial remuneration was not evident in these patients of whom seven were not even seeking payments of any kind. This study suggests that these hitherto unrecognized post-traumatic headaches constitute a class of headaches characterized by a relation to traumatic events affecting the body but not including head or whiplash traumas. The bodily injuries per se can be discounted as the cause of the headaches. So can fabrication of symptoms for financial remuneration. Altered mental states, not systematically evaluated here, were a possible cause of the headaches. The overall resemblance of these headaches to the headaches after head or whiplash traumas implies that these latter two headache types may likewise not be products of structural injuries.


Broadband High-Efficiency Chiral Splitters and Holograms from Dielectric Nanoarc Metasurfaces.
Simultaneous broadband and high efficiency merits of designer metasurfaces are currently attracting widespread attention in the field of nanophotonics. However, contemporary metasurfaces rarely achieve both advantages simultaneously. For the category of transmissive metadevices, plasmonic or conventional dielectric metasurfaces are viable for either broadband operation with relatively low efficiency or high efficiency at only a selection of wavelengths. To overcome this limitation, dielectric nanoarcs are proposed as a means to accomplish two advantages. Continuous nanoarcs support different electromagnetic resonant modes at localized areas for generating phase retardation. Meanwhile, the geometric nature of nanoarc curvature endows the nanoarcs with full phase coverage of 0-2π due to the Pancharatnam-Berry phase principle. Experimentally incorporated with the chiral-detour phase principle, a few compelling functionalities are demonstrated, such as chiral beamsplitting, broadband holography, and helicity-selective holography. The continuous nanoarc metasurfaces prevail over plasmonic or dielectric discretized building block strategies and the findings lead to novel designs of spin-controllable metadevices.


Lipoadenoma of the parathyroid gland - a rare cause of hyperparathyroidism.
Lipoadenoma of parathyroid gland is an unusual morphologic variant of parathyroid adenoma in which the glandular elements are associated with abundant mature adipose tissue. The lesion has also been reported as parathyroid lipohyperplasia, parathyroid hamartoma, and parathyroid adenoma with myxoid stroma. Most cases are functioning and are associated with hyperparathyroidism. Lipoadenoma of parathyroid gland are difficult to diagnose as a cause of hyperparathyroidism because of rarity of these lesions and overlap with normal parathyroid tissue on microscopic evaluation. Only few cases have been documented in the literature so far. The lesion may be overlooked by both surgeon and pathologists alike, if they are not aware of this specific clinicopathologic entity.


Search for Gravitational Waves from High-Mass-Ratio Compact-Binary Mergers of Stellar Mass and Subsolar Mass Black Holes.
We present the first search for gravitational waves from the coalescence of stellar mass and subsolar mass black holes with masses between 20-100 M_{⊙} and 0.01-1 M_{⊙}(10-10^{3} M_{J}), respectively. The observation of a single subsolar mass black hole would establish the existence of primordial black holes and a possible component of dark matter. We search the ∼164 day of public LIGO data from 2015-2017 when LIGO-Hanford and LIGO-Livingston were simultaneously observing. We find no significant candidate gravitational-wave signals. Using this nondetection, we place a 90% upper limit on the rate of 30-0.01 M_{⊙} and 30-0.1 M_{⊙} mergers at <1.2×10^{6} and <1.6×10^{4} Gpc^{-3} yr^{-1}, respectively. If we consider binary formation through direct gravitational-wave braking, this kind of merger would be exceedingly rare if only the lighter black hole were primordial in origin (<10^{-4} Gpc^{-3} yr^{-1}). If both black holes are primordial in origin, we constrain the contribution of 1(0.1)M_{⊙} black holes to dark matter to <0.3(3)%.


Treg Therapies Revisited: Tolerance Beyond Deletion.
Induction of immune tolerance is the Holy Grail in transplantation medicine and autoimmunity. Currently, patients are required to use immunosuppressive drugs for the rest of their lives, resulting in unwanted side effects and complication from global suppression of the immune response. It is well established that regulatory T cells (Tregs) are critical for the maintenance of immune tolerance towards self-antigens by several mechanisms of immune regulation, in parallel with intrathymic deletion of self-reactive T cells during ontogeny. Therefore, approaches for increasing Treg numbers or function in vivo could provide an all-purpose solution for tolerance induction. Currently, most state-of-the-art therapeutics for treating autoimmune diseases or preventing allograft rejection work either by general immunosuppression or blocking inflammatory reactions and are non-specific. Hence, these approaches cannot provide satisfactory long-term results, let alone a cure. However, in animal models the therapeutic potential of Treg expansion for inducing effective tolerance has now been demonstrated in various models of autoimmunity and allogeneic transplantation. Here, we focus on therapies for increasing the size of the Treg pool by expanding endogenous Treg numbers in vivo or by adoptive transfer of Tregs. In particular, we discuss IL-2 based approaches (low dose IL-2, IL-2 complexes) for inducing Treg expansion in vivo as well as cell-based approaches (polyclonal, antigen specific, or cell engineered) for adoptive Treg therapy. We also mention new questions arising from the first clinical studies on Treg therapy in the fields of transplantation and autoimmunity.


Induction of apoptosis in human non-small cell lung carcinoma cells by the novel synthetic retinoid CD437.
Retinoids are promising agents for the prevention and treatment of several human malignancies including lung cancer. However, many lung cancer cell lines are resistant to the growth inhibitory effects of all-trans-retinoic acid (ATRA). Recently, we found that a new synthetic retinoid, 6-[3-(1-adamantyl)-4-hydroxyphenyl]-2-naphthalene carboxylic acid (CD437), which binds selectively to nuclear RA receptor gamma, was the most effective inhibitor of the growth of human non-small cell lung carcinoma (NSCLC) cells among 37 retinoids tested. After a 4-day treatment with CD437 the growth of 8 NSCLC cell lines was inhibited with an IC50 ranging from 0.13 to 0.53 microM. In contrast, ATRA failed to inhibit the growth of any of these cell lines by more than 43% after a 7-day treatment even at 10 microM. The presence of detached rounded cells in treated cultures indicated that CD437 may induce apoptosis. Indeed, this was confirmed by the presence of 20-57% cells with a sub-G1 DNA content and by an enzyme-linked immunosorbent assay (ELISA) of apoptosis. Two retinoids, CD2366 and CD2665, which are antagonists of nuclear retinoid receptor activation, failed to inhibit the effect of CD437 on the growth of the NSCLC cell lines. CD437 failed to suppress the transcriptional activation of the activator protein-1 (AP-1) reporter. These results demonstrate that CD437 can induce apoptosis in NSCLC cells that are resistant to ATRA and that this effect is mediated by a mechanism that may be independent of transactivation of retinoid receptors or transrepression of AP-1.


Use of primary health care prior to a postpartum psychiatric episode.
Childbirth is a strong trigger of psychiatric episodes. Nevertheless, use of primary care before these episodes is not quantified. The aim was to study the use of general practice in Denmark from two years before to one year after childbirth in women who developed postpartum psychiatric disorders. A matched cohort study was conducted including women who gave birth in the period 1996-2010. Women were divided into four groups: (i) all mothers with postpartum psychiatric episodes 0-3 months after birth, n = 939; 2: All mothers with a postpartum psychiatric episode 3-12 months after birth, n = 1 436; and (iii) two comparison groups of mothers, total n = 6 630 among 320 620 eligible women. Denmark. Women born in Denmark after 1 January 1960, restricting the cohort to women who gave birth to their first singleton child between 1 January 1996 and 20 October 2010. The main outcome measures were consultation rates, consultation rate ratios, and rate differences. Women who developed a psychiatric episode after childbirth had higher GP consultation rates before, during, and after the pregnancy. Women with a psychiatric episode 0-3 months postpartum had 6.89 (95% CI 6.60; 7.18) mean number of consultations during pregnancy, corresponding to 1.52 (95% CI 1.22; 1.82) more visits than the comparison group. Women with a postpartum psychiatric episode had higher use of GP-based primary health care services years before the childbirth, and in this specific group of patients childbirth itself triggered a marked increase in the number of GP contacts postpartum.


Pericardial synovial sarcoma of the heart; is it always worth operating?
Synovial sarcoma is a rare malignant soft-tissue tumor that most commonly occurs in the extremities of young adults. Primary pericardial synovial sarcoma is extremely rare. We report the case of a 37 year old male patient who presented with intermittent fever, nocturnal sweating and asthenia. Chest X-ray revealed an enlarged cardiac silhouette. Echocardiography identified pericardial effusion and a mass compressing the right ventricle. After percutaneous drainage of the effusion, the mass was not visible and deemed to have been septations of the effusion. Chest computed tomography (CT) did not show the mass visible on the X-ray. At one month follow-up, the pericardial mass was again visible on echocardiography and confirmed by magnetic resonance imaging (MRI). CT-guided biopsy showed malignant mesenchymal cells. Complete resection was attempted, but not possible due to diffuse infiltration of the epicardium. Histological examination of the resected tissue revealed an undifferentiated primary pericardial synovial sarcoma. The patient refused adjuvant treatment and died 15 days later. Surgical resection is considered the cornerstone of treatment of this rare type of malignant tumor of the young; our patient presented with a diffusely infiltrating tumor which could not be resected and required reoperation for tamponade and left pericardectomy. We question whether the choice to attempt resection was beneficial.


Innate-Immunity Genes in Obesity.
The main functions of adipose tissue are thought to be storage and mobilization of the body's energy reserves, active and passive thermoregulation, participation in the spatial organization of internal organs, protection of the body from lipotoxicity, and ectopic lipid deposition. After the discovery of adipokines, the endocrine function was added to the above list, and after the identification of crosstalk between adipocytes and immune cells, an immune function was suggested. Nonetheless, it turned out that the mechanisms underlying mutual regulatory relations of adipocytes, preadipocytes, immune cells, and their microenvironment are complex and redundant at many levels. One possible way to elucidate the picture of adipose-tissue regulation is to determine genetic variants correlating with obesity. In this review, we examine various aspects of adipose-tissue involvement in innate immune responses as well as variants of immune-response genes associated with obesity.


Carbon Encapsulated Tin Oxide Nanocomposites: An Efficient Anode for High Performance Sodium-Ion Batteries.
The major obstacle in realizing sodium (Na)-ion batteries (NIBs) is the absence of suitable negative electrodes. This is because graphite, a commercially well known anode material for lithium-ion batteries, cannot be utilized as an insertion host for Na ions due to its large ionic size. In this study, a simple and cost-effective hydrothermal method to prepare carbon coated tin oxide (SnO2) nanostructures as an efficient anode material for NIBs was reported as a function of the solvent used. A single phase SnO2 resulted for the ethanol solvent, while a blend of SnO and SnO2 resulted for the DI water and ethylene glycol solvents. The elemental mapping in the transmission electron microscopy confirmed the presence of carbon coating on the SnO2 nanoparticles. In cell tests, the anodes of carbon coated SnO2 prepared in ethanol solvent exhibited stable cycling performance and attained a capacity of about 514 mAh g(-1) on the first charge. With the help of the conductive carbon coating, the SnO2 delivers more capacity at high rates: 304 mAh g(-1) at the 1 C rate, 213 mAh g(-1) at the 2 C rate and 133 mAh g(-1) at the 5 C rate. The excellent cyclability and high rate capability are the result of the formation of a mixed conducting network and uniform carbon coating on the SnO2 nanoparticles.


Immunogenicity and safety of an inactivated hepatitis A vaccine amongst Singaporeans.
The immunogenicity and reactogenicity of an inactivated hepatitis A virus (HAV) vaccine was studied in healthy Singaporean adult volunteers. One hundred and forty healthy volunteers with normal alanine (ALT) and aspartate (AST) transaminases and no previous exposure to HAV, received three 1 ml doses (720 ELISA units) of an inactivated HAV vaccine (Smithkline Beechams Biologicals) following a 0, 1, 6 months vaccination schedule. All subjects were asked to record and grade the severity of any reactions for three consecutive days after each dose. Serum ALT and AST as well as anti-HAV were measured at 0, 1, 2, 6 and 7 months after the first vaccine dose. Anti-HAV seroconversion occurred when levels rose above 40 mIU/ml. Eighty-five percent of vaccinees seroconverted after the first innoculation and 99% after the second injection. All vaccinees seroconverted after the third dose. Geometric mean anti-HAV titers (GMTs) were, respectively, 119, 391, 4406 mIU/ml one month after each of the three doses. The most common side effect was transient pain and tenderness at the vaccination site. No elevation of ALT or AST levels were noted during the study period. The inactivated hepatitis A vaccine used in this study is safe and highly immunogenic in the local adult population. Two doses one month apart appeared to give adequate protection.


Control measures following a case of imported Lassa fever from Togo, North Rhine Westphalia, Germany, 2016.
In a patient transferred from Togo to Cologne, Germany, Lassa fever was diagnosed 12 days post mortem. Sixty-two contacts in Cologne were categorised according to the level of exposure, and gradual infection control measures were applied. No clinical signs of Lassa virus infection or Lassa specific antibodies were observed in the 62 contacts. Thirty-three individuals had direct contact to blood, other body fluids or tissue of the patients. Notably, with standard precautions, no transmission occurred between the index patient and healthcare workers. However, one secondary infection occurred in an undertaker exposed to the corpse in Rhineland-Palatinate, who was treated on the isolation unit at the University Hospital of Frankfurt. After German authorities raised an alert regarding the imported Lassa fever case, an American healthcare worker who had cared for the index patient in Togo, and who presented with diarrhoea, vomiting and fever, was placed in isolation and medevacked to the United States. The event and the transmission of Lassa virus infection outside of Africa underlines the need for early diagnosis and use of adequate personal protection equipment (PPE), when highly contagious infections cannot be excluded. It also demonstrates that larger outbreaks can be prevented by infection control measures, including standard PPE.


Predictive Value of Respiratory Viral Detection in the Upper Respiratory Tract for Infection of the Lower Respiratory Tract With Hematopoietic Stem Cell Transplantation.
Hematopoietic cell transplant (HCT) recipients are frequently infected with respiratory viruses (RVs) in the upper respiratory tract (URT), but the concordance between URT and lower respiratory tract (LRT) RV detection is not well characterized. Hematopoietic cell transplant candidates and recipients with respiratory symptoms and LRT and URT RV testing via multiplex PCR from 2009 to 2016 were included. Logistic regression models were used to analyze risk factors for LRT RV detection. Two-hundred thirty-five HCT candidates or recipients had URT and LRT RV testing within 3 days. Among 115 subjects (49%) positive for a RV, 37% (42 of 115) had discordant sample pairs. Forty percent (17 of 42) of discordant pairs were positive in the LRT but negative in the URT. Discordance was common for adenovirus (100%), metapneumovirus (44%), rhinovirus (34%), and parainfluenza virus type 3 (28%); respiratory syncytial virus was highly concordant (92%). Likelihood of LRT detection was increased with URT detection (oods ratio [OR] = 73.7; 95% confidence interval [CI], 26.7-204) and in cytomegalovirus-positive recipients (OR = 3.70; 95% CI, 1.30-10.0). High rates of discordance were observed for certain RVs. Bronchoalveolar lavage sampling may provide useful diagnostic information to guide management in symptomatic HCT candidates and recipients.


Platelet-directed antibody in the serum of patients with primary thrombotic thrombocytopenic purpura.
Utilizing two platelet antibody assay systems, flow cytometric analysis and a microcytotoxicity assay, it was possible to demonstrate for the first time platelet-directed antibody in the sera of three of six patients with primary thrombotic thrombocytopenic purpura. These results lend support for an immune-mediated pathologic process in some patients with this disorder.


Accessory cells with immunophenotypic and functional features of monocyte-derived dendritic cells are recruited to the lung during pulmonary inflammation.
Pulmonary macrophages (Mphi) increase in tissue and bronchoalveolar lavage (BAL) fluid during inflammation caused by bleomycin (BLM). This study demonstrates that increasing numbers of exudate Mphi in BLM lung injury exhibit dendritic cell (DC) features. After the intratracheal administration of BLM (0.075 U), adherent mononuclear cells from the bronchoalveolar lavage fluid (BAMC) of C57BL/6 mice were characterized for morphology, immunophenotype, and accessory cell activities. At day 7 post-BLM, 48% of CD11b+ BAMC displayed features of DC differentiation, as judged by dendritic morphology, expression of class II MHC, 33D1, Factor XIIIa, CD80, and CD86 antigens, and the ability to support a primary allogeneic lymphocyte response (MLR). After BLM treatment, CD11b+ peripheral blood monocytes also showed increased expression of 33D1, Factor XIIIa, CD86, and the ability to stimulate an MLR. We conclude that inflammatory DC with immunophenotypic features of monocyte-derived DC increase in the peripheral blood and lung after an inflammatory stimulus.